N,n-substituted 3-aminopyrrolidine compounds useful as monoamines reuptake inhibitors

ABSTRACT

The present invention provides a pyrrolidine compound of General Formula (1) 
     
       
         
         
             
             
         
       
     
     or a salt thereof, wherein R 101  and R 102  are each independently a phenyl group or a pyridyl group, the phenyl group or the pyridyl group may have one or more substituents selected from halogen atoms and lower alkyl groups optionally substituted with one or more halogen atoms, etc. The pyrrolidine compound or a salt thereof of the present invention is usable to produce a pharmaceutical preparation having a wider therapeutic spectrum and being capable of exhibiting sufficient therapeutic effects after short-term administration.

This is a Divisional Appln. of U.S. application Ser. No. 11/914,183,filed Sep. 29, 2008, which is a National Stage Entry ofPCT/JP2006/309988, filed May 12, 2006, claiming priority from JP Appln.No. 2005-141230, filed May 13, 2005, the contents of all of which areincorporated herein by reference in their entirety.

TECHNICAL FIELD

The present invention relates to a pyrrolidine compound.

BACKGROUND OF THE INVENTION

Three types of monoamines, known as serotonin, norepinephrine anddopamine, act as neurotransmitters in organisms. Therefore,pharmaceuticals having a monoamine reuptake inhibitory effect are widelyused as therapeutic pharmaceuticals for diseases of the central andperipheral nervous systems.

Many of the pharmaceuticals used to date for treating depressionselectively inhibit norepinephrine or serotonin reuptake. Examples ofsuch pharmaceuticals include imipramine (a first-generationantidepressant), maprotiline (a second-generation antidepressant),selective serotonin-uptake inhibitors such as fluoxetine (SSRI,third-generation antidepressants), serotonin and/or norepinephrinereuptake inhibitors such as venlafaxine (SNRI,fourth-generation-antidepressants), and the like (see Sadanori Miura,Rinshoseishinyakuri (Japanese Journal of Clinical Psychopharmacology),2000, 3: 311-318).

However, it takes at least three weeks for these pharmaceuticals toexhibit their therapeutic effects and furthermore, these pharmaceuticalsfail to exhibit sufficient effects in about 30% of patients sufferingfrom depression (see Phil Skolnick, European Journal of Pharmacology,2001, 375: 31-40).

DISCLOSURE OF THE INVENTION

An object of the invention is to provide a pharmaceutical preparationhaving a wider therapeutic spectrum than known antidepressants, andbeing capable of exhibiting sufficient therapeutic effects aftershort-term administration.

The present inventors carried out extensive research to achieve theabove object and found that a pyrrolidine compound represented byformula (1) below can be used to produce such a desired pharmaceuticalpreparation. The present invention has been accomplished based on thisfinding.

The present invention provides a pyrrolidine compound, a compositioncomprising said compound, an agent comprising said compound, a use ofsaid compound, a method for treating a disorder, and a process forproducing said compound, as described in Items 1 to 14 below.

Item 1. A pyrrolidine compound of General Formula (1)

or a salt thereof,wherein R¹⁰¹ and R¹⁰² are each independently one of the following groups(1) to (86):(1) a phenyl group,(2) a pyridyl group,(3) a benzothienyl group,(4) an indolyl group,(5) a 2,3-dihydro-1H-indenyl group,(6) a naphthyl group,(7) a benzofuryl group,(8) a quinolyl group,(9) a thiazolyl group,(10) a pyrimidinyl group,(11) a pyrazinyl group,(12) a benzothiazolyl group,(13) a thieno[3,2-b]pyridyl group,(14) a thienyl group,(15) a cycloalkyl group,(16) a tetrahydropyranyl group,(17) a pyrrolyl group,(18) a 2,4-dihydro-1,3-benzodioxinyl group,(19) a 2,3-dihydrobenzofuryl group,(20) a 9H-fluorenyl group,(21) a pyrazolyl group,(22) a pyridazinyl group,(23) an indolinyl group,(24) a thieno[2,3-b]pyridyl group,(25) a thieno[3,2-d]pyrimidinyl group,(26) a thieno[3,2-e]pyrimidinyl group,(27) a 1H-pyrazolo[3,4-b]pyridyl group,(28) an isoquinolyl group,(29) a 2,3-dihydro-1,4-benzoxadinyl group,(30) a quinoxalinyl group,(31) a quinazolinyl group,(32) a 1,2,3,4-tetrahydroquinolyl group,(33) a cycloalkyl lower alkyl group,(34) a lower alkylthio lower alkyl group,(35) an amino-substituted lower alkyl group optionally substituted withone or two lower alkyl groups on the amino group,(36) a phenoxy lower alkyl group,(37) a pyridyloxy lower alkyl group,(38) a lower alkynyl group,(39) a phenyl lower alkenyl group,(40) a 1,3-benzodioxolyl group,(41) a 2,3-dihydro-1,4-benzodioxinyl group,(42) a 3,4-dihydro-1,5-benzodioxepinyl group,(43) a dihydropyridyl group,(44) a 1,2-dihydroquinolyl group,(45) a 1,2,3,4-tetrahydroisoquinolyl group,(46) a benzoxazolyl group,(47) a benzoisothiazolyl group,(48) an indazolyl group,(49) a benzoimidazolyl group,(50) an imidazolyl group,(51) a 1,2,3,4-tetrahydronaphthyl lower alkyl group,(52) an imidazo[1,2-a]pyridyl lower alkyl group,(53) a thiazolyl lower alkyl group,(54) a tetrahydropyranyl lower alkyl group,(55) a piperidyl lower alkyl group,(56) a diphenyl lower alkoxy-substituted lower alkyl group,(57) a lower alkoxycarbonyl-substituted lower alkyl group,(58) a phenyl lower alkoxycarbonyl-substituted lower alkyl group,(59) a hydroxy-substituted lower alkyl group,(60) a lower alkoxy lower alkyl group,(61) a carboxy lower alkyl group,(62) a carbamoyl-substituted lower alkyl group optionally substitutedwith one or two lower alkyl groups on the carbamoyl group,(63) a lower alkenyl group,(64) a morpholinylcarbonyl lower alkyl group,(65) a benzoyl lower alkyl group,(66) a phenylthio lower alkyl group,(67) a naphthylthio lower alkyl group,(68) a cycloalkylthio lower alkyl group,(69) a pyridylthio lower alkyl group,(70) a pyrimidinylthio lower alkyl group,(71) a furylthio lower alkyl group,(72) a thienylthio lower alkyl group,(73) a 1,3,4-thiadiazolylthio lower alkyl group,(74) a benzimidatolylthio lower alkyl group,(75) a benzthiazolylthio lower alkyl group,(76) a tetrazolylthio lower alkyl group,(77) a benzoxazolylthio lower alkyl group,(78) a thiazolylthio lower alkyl group,(79) an imidazolylthio lower alkyl group,(80) an amino-substituted lower alkylthio lower alkyl group optionallysubstituted with one or two lower alkyl groups on the amino group,(81) a phenyl-substituted lower alkylthio lower alkyl group,(82) a furyl-substituted lower alkylthio lower alkyl group,(83) a pyridyl-substituted lower alkylthio lower alkyl group,(84) a hydroxy-substituted lower alkylthio lower alkyl group,(85) a phenoxy-substituted lower alkylthio lower alkyl group, and(86) a lower alkoxycarbonyl-substituted lower alkylthio lower alkylgroup,and each of the groups (1) to (32), (37), (39) to (56), (64) to (79),(81) to (83) and (85) may have one or more substituents selected fromthe following (1-1) to (1-37) on the cycloalkyl, aromatic orheterocyclic ring:(1-1) halogen atoms,(1-2) lower alkylthio groups optionally substituted with one or morehalogen atoms,(1-3) lower alkyl groups optionally substituted with one or more halogenatoms,(1-4) lower alkoxy groups optionally substituted with one or morehalogen atoms,(1-5) nitro group,(1-6) lower alkoxycarbonyl groups,(1-7) amino groups optionally substituted with one or two lower alkylgroups,(1-8) lower alkylsulfonyl groups,(1-9) cyano group,(1-10) carboxy group,(1-11) hydroxy group,(1-12) thienyl groups,(1-13) oxazolyl groups,(1-14) naphthyl groups,(1-15) benzoyl group,(1-16) phenoxy groups optionally substituted with one to three halogenatoms on the phenyl ring,(1-17) phenyl lower alkoxy groups,(1-18) lower alkanoyl groups,(1-19) phenyl groups optionally substituted on the phenyl ring with oneto five substituents selected from the group consisting of halogenatoms, lower alkoxy groups, cyano group, lower alkanoyl groups and loweralkyl groups,(1-20) phenyl lower alkyl groups,(1-21) cyano lower alkyl groups,(1-22) 5 to 7-membered saturated heterocyclic group-substituted sulfonylgroups, the heterocyclic group containing on the heterocyclic ring oneor two heteroatoms selected from the group consisting of nitrogen,oxygen and sulfur,(1-23) thiazolyl groups optionally substituted with one or two loweralkyl groups on the thiazole ring,(1-24) imidazolyl groups,(1-25) amino lower alkyl groups optionally substituted with one or twolower alkyl groups on the amino group,(1-26) pyrrolidinyl lower alkoxy groups,(1-27) isoxazolyl groups,(1-28) cycloalkylcarbonyl groups,(1-29) naphthyloxy groups,(1-30) pyridyl groups,(1-31) furyl groups,(1-32) phenylthio group,(1-33) oxo group,(1-34) carbamoyl group,(1-35) 5 to 7-membered saturated heterocyclic groups containing one ortwo heteroatoms selected from the group consisting of nitrogen, oxygenand sulfur, the heterocyclic group optionally being substituted with oneto three substituents selected from the group consisting of oxo group;lower alkyl groups; lower alkanoyl groups; phenyl lower alkyl groups;phenyl groups optionally substituted on the phenyl ring with one tothree members selected from the group consisting of halogen atoms andlower alkoxy groups; and pyridyl groups,(1-36) oxido group and(1-37) lower alkoxido groups,with the proviso that R¹⁰¹ and R¹⁰² are not simultaneously unsubstitutedphenyl.

Item 2. A pyrrolidine compound of General Formula (1) or a salt thereofaccording to Item 1, wherein

R¹⁰¹ is

(1) a phenyl group,(3) a benzothienyl group,(4) an indolyl group,(5) a 2,3-dihydro-1H-indenyl group,(6) a naphthyl group,(7) a benzofuryl group,(8) a quinolyl group,(12) a benzothiazolyl group,(18) a 2,4-dihydro-1,3-benzodioxinyl group,(19) a 2,3-dihydrobenzofuryl group,(20) a 9H-fluorenyl group,(23) an indolinyl group,(28) an isoquinolyl group,(29) a 2,3-dihydro-1,4-benzoxadinyl group,(30) a quinoxalinyl group,(31) a quinazolinyl group,(32) a 1,2,3,4-tetrahydroquinolyl group,(40) a 1,3-benzodioxolyl group,(41) a 2,3-dihydro-1,4-benzodioxinyl group,(42) a 3,4-dihydro-1,5-benzodioxepinyl group,(44) a 1,2-dihydroquinolyl group,(45) a 1,2,3,4-tetrahydroisoquinolyl group,(46) a benzoxazolyl group,(47) a benzoisothiazolyl group,(48) an indazolyl group or(49) a benzoimidazolyl group,and each of which may have on the aromatic or heterocyclic ring one tothree substituents selected from the groups (1-1) to (1-37) as definedin Item 1.

Item 3. A pyrrolidine compound of General Formula (1) or a salt thereofaccording to Item 2, wherein

R¹⁰¹ is

(1) a phenyl group or(3) a benzothienyl group,and each of which may have on the aromatic or heterocyclic ring one tothree substituents selected from the group consisting of (1-1) halogenatoms and (1-3) lower alkyl groups optionally substituted with one tothree halogen atoms.

Item 4. A pyrrolidine compound of General Formula (1) or a salt thereofaccording to Item 3, wherein

R¹⁰² is

(1) a phenyl group,(2) a pyridyl group,(9) a thiazolyl group,(10) a pyrimidinyl group,(11) a pyrazinyl group(14) a thienyl group,(48) an indazolyl group,(59) a hydroxy-substituted lower alkyl group or(60) a lower alkoxy lower alkyl group,and each of the groups (1), (2), (9), (10), (11), (14) and (48) may haveon the aromatic or heterocyclic ring one to three substituents selectedfrom the groups (1-1) to (1-37) as defined in Item 1.

Item 5. A pyrrolidine compound of General Formula (1) or a salt thereofaccording to Item 4, wherein

R¹⁰¹ is

a monohalophenyl group, a dihalophenyl group or a phenyl groupsubstituted with one halogen atom and one lower alkyl group,

R¹⁰² is

(1) a phenyl group,(2) a pyridyl group,(9) a thiazolyl group,(10) a pyrimidinyl group,(11) a pyrazinyl group,(14) a thienyl group,(48) an indazolyl group,(59) a hydroxy-substituted lower alkyl group or(60) a lower alkoxy lower alkyl group,and each of the groups (1), (2), (9), (10), (11), (14) and (48) may haveon the aromatic or heterocyclic ring one or two substituents selectedfrom the group consisting of (1-1) halogen atoms, (1-3) lower alkylgroups optionally substituted with one or more halogen atoms, and (1-9)cyano group.

Item 6. A pyrrolidine compound of General Formula (1) or a salt thereofaccording to Item 5 selected from the group consisting of:

-   (4-chlorophenyl)phenyl-(S)-pyrrolidin-3-ylamine,-   (4-fluorophenyl)phenyl-(S)-pyrrolidin-3-ylamine,-   (3,4-difluorophenyl)phenyl-(S)-pyrrolidin-3-ylamine,-   bis-(4-fluorophenyl)-(S)-pyrrolidin-3-ylamine,-   (3,4-difluorophenyl)-(4-fluorophenyl)-(S)-pyrrolidin-3-ylamine,-   (3-chloro-4-fluorophenyl)-(S)-pyrrolidin-3-yl-p-tolylamine,-   4-[(S)-(4-fluoro-3-methylphenyl) pyrrolidin-3-ylamino]-benzonitrile,-   bis-(3-fluorophenyl)-(S)-pyrrolidin-3-ylamine,-   (3-chloro-4-fluorophenyl)-(S)-pyrrolidin-3-ylthiazol-2-ylamine,-   (4-fluorophenyl)-(S)-pyrrolidin-3-ylthiazol-2-ylamine,-   (3,4-dichlorophenyl)-(S)-pyrrolidin-3-ylthiazol-2-ylamine,-   (3,4-dichlorophenyl)pyrimidin-5-yl-(S)-pyrrolidin-3-ylamine,-   (3-chloro-4-fluorophenyl)pyrazin-2-yl-(S)-pyrrolidin-3-ylamine,-   (3-chloro-4-fluorophenyl)-(5-chloropyridin-2-yl)-(S)-pyrrolidin-3-ylamine,-   (3-chloro-4-fluorophenyl)pyridin-2-yl-(S)-pyrrolidin-3-ylamine,-   (3-chloro-4-fluorophenyl)pyridin-3-yl-(S)-pyrrolidin-3-ylamine,-   (3-chloro-4-fluorophenyl)-(6-fluoropyridin-3-yl)-(S)-pyrrolidin-3-ylamine,-   (3,4-dichlorophenyl)pyridin-3-yl-(S)-pyrrolidin-3-ylamine,-   (3-chloro-4-fluorophenyl)-(S)-pyrrolidin-3-ylthiophen-3-ylamine,-   (3-chloro-4-fluorophenyl)-(5-fluoropyridin-3-yl)-(S)-pyrrolidin-3-ylamine,-   (4-fluoro-3-methylphenyl)-(5-fluoropyridin-3-yl)-(S)-pyrrolidin-3-ylamine,-   2-[(S)-(3-chloro-4-fluorophenyl)pyrrolidin-3-ylamino]ethanol,-   1-[(S)-(3-chloro-4-fluorophenyl)pyrrolidin-3-ylamino]-2-methyl-propan-2-ol,-   (3-chloro-4-fluorophenyl)-(2-methoxyethyl)-(S)-pyrrolidin-3-ylamine,-   3-[(S)-(3-chloro-4-fluorophenyl)pyrrolidin-3-ylamino]-propan-1-ol,-   (3-chloro-4-fluorophenyl)-(3-methoxypropyl)-(S)-pyrrolidin-3-ylamine,-   (3-chloro-4-fluorophenyl)-(1-methyl-1H-indazol-5-yl)-(S)-pyrrolidin-3-ylamine,-   benzo[b]thiophen-6-yl-(S)-pyrrolidin-3-ylthiophen-3-ylamine, and-   benzo[b]thiophen-5-yl-(S)-pyrrolidin-3-ylthiophen-3-ylamine.

Item 7. A pharmaceutical composition comprising a pyrrolidine compoundof General Formula (1) or a salt thereof according to Item 1 as anactive ingredient and a pharmaceutically acceptable carrier.

Item 8. A prophylactic and/or therapeutic agent for disorders caused byreduced neurotransmission of serotonin, norepinephrine or dopamine,comprising as an active ingredient a pyrrolidine compound of GeneralFormula (1) or a salt thereof according to Item 1.

Item 9. A prophylactic and/or therapeutic agent according to Item 8,wherein the disorder is selected from the group consisting ofhypertension; depression; anxiety disorders; fear; posttraumatic stresssyndrome; acute stress syndrome; avoidant personality disorders; bodydysmorphic disorder; precocious ejaculation; eating disorders; obesity;chemical dependencies to alcohol, cocaine, heroin, phenobarbital,nicotine and benzodiazepines; cluster headache; migraine; pain disorder;Alzheimer's disease; obsessive-compulsive disorders; panic disorders;memory disorders; Parkinson's disease; endocrine disorders; vascularspasm; cerebellar ataxia; gastrointestinal tract disorders; negativesyndrome of schizophrenia; premenstrual syndrome; fibromyalgia syndrome;stress incontinence; Tourette's syndrome; trichotillomania; kleptomania;male impotence; attention deficit hyperactivity disorder (ADHD); chronicparoxysmal hemicrania; chronic fatigue; cataplexy; sleep apnea syndromeand headache.

Item 10. A prophylactic and/or therapeutic agent according to Item 8,wherein the disorder is selected from the group consisting of:

depressions selected from the group consisting of major depression;bipolar 1 disorder; bipolar 2 disorder; mixed episode; dysthymicdisorders; rapid cycler; atypical depression; seasonal affectivedisorders; postpartum depression; minor depression; recurrent briefdepressive disorder; intractable depression/chronic depression; doubledepression; alcohol-induced mood disorders; mixed anxiety & depressivedisorders; depressions induced by various physical disorders selectedfrom the group consisting of Cushing's disease, hypothyroidism,hyperparathyroidism syndrome, Addison's disease, amenorrhea andlactation syndrome, Parkinson's disease, Alzheimer's disease,intracerebral bleeding, diabetes, chronic fatigue syndrome and cancers;depression of the middle-aged; senile depression; depression of childrenand adolescents; depression induced by interferons; depression inducedby adjustment disorder; and anxieties selected from the group consistingof anxiety induced by adjustment disorder and anxiety induced byneuropathy selected from the group consisting of head trauma, braininfection and inner ear injury.

Item 11. Use of a pyrrolidine compound of General Formula (1) or a saltthereof according to any one of Items 1 to 6 as a drug.

Item 12. Use of a pyrrolidine compound of General Formula (1) or a saltthereof according to any one of Items 1 to 6 as a serotonin reuptakeinhibitor and/or a norepinephrine reuptake inhibitor and/or a dopaminereuptake inhibitor.

Item 13. A method for treating or preventing disorders caused by reducedneurotransmission of serotonin, norepinephrine or dopamine, comprisingadministering a pyrrolidine compound of General Formula (1) or a saltthereof according to any one of Items 1 to 6 to human or animal.

Item 14. A process for producing a pyrrolidine compound of GeneralFormula (1):

or a salt thereof, wherein R¹⁰¹ and R¹⁰² are defined above in Item 1,

the process comprising

(1) subjecting a compound of General Formula (2)

wherein R¹⁰¹ and R¹⁰² are as defined above in Item 1, and R¹¹² is anamino-protecting group to an elimination reaction to remove the aminoprotecting group.

Preferred embodiments of the pyrrolidine compound (1) include compoundsrepresented by General Formula (1)

and salts thereof,wherein R¹⁰¹ is(1) a phenyl group,(3) a benzothienyl group,(4) an indolyl group,(5) a 2,3-dihydro-1H-indenyl group,(6) a naphthyl group,(7) a benzofuryl group,(8) a quinolyl group,(12) a benzothiazolyl group,(18) a 2,4-dihydro-1,3-benzodioxinyl group,(19) a 2,3-dihydrobenzofuryl group,(20) a 9H-fluorenyl group,(23) an indolinyl group,(28) an isoquinolyl group,(29) a 2,3-dihydro-1,4-benzoxadinyl group,(30) a quinoxalinyl group,(31) a quinazolinyl group,(32) a 1,2,3,4-tetrahydroquinolyl group,(40) a 1,3-benzodioxolyl group,(41) a 2,3-dihydro-1,4-benzodioxinyl group,(42) a 3,4-dihydro-1,5-benzodioxepinyl group,(44) a 1,2-dihydroquinolyl group,(45) a 1,2,3,4-tetrahydroisoquinolyl group,(46) a benzoxazolyl group,(47) a benzoisothiazolyl group,(48) an indazolyl group or(49) a benzoimidazolyl group,and each of which may have on the aromatic or heterocyclic ring one tofive (preferably one to three) substituents selected from the following(1-1) to (1-37):(1-1) halogen atoms,(1-2) lower alkylthio groups optionally substituted with one or more(preferably one to three) halogen atoms,(1-3) lower alkyl groups optionally substituted with one or more(preferably one to three) halogen atoms,(1-4) lower alkoxy groups optionally substituted with one or more(preferably one to four) halogen atoms,(1-5) nitro group,(1-6) lower alkoxycarbonyl groups,(1-7) amino groups optionally substituted with one or two lower alkylgroups,(1-8) lower alkylsulfonyl groups,(1-9) cyano group,(1-10) carboxy group,(1-11) hydroxy group,(1-12) thienyl groups,(1-13) oxazolyl groups,(1-14) naphthyl groups,(1-15) benzoyl group,(1-16) phenoxy groups optionally substituted with one to three halogenatoms on phenyl ring,(1-17) phenyl lower alkoxy groups,(1-18) lower alkanoyl groups,(1-19) phenyl groups optionally substituted on the phenyl ring with oneto five (preferably one to three) substituents selected from the groupconsisting of halogen atoms, lower alkoxy groups, cyano group, loweralkanoyl groups and lower alkyl groups,(1-20) phenyl lower alkyl groups,(1-21) cyano lower alkyl groups,(1-22) 5 to 7-membered saturated heterocyclic group-substituted sulfonylgroups, the heterocyclic group containing on the heterocyclic ring oneor two nitrogen atoms (preferably piperidylsulfonyl),(1-23) thiazolyl groups optionally substituted with one or two loweralkyl groups on the thiazole ring,(1-24) imidazolyl groups,(1-25) amino lower alkyl groups optionally substituted with one or twolower alkyl groups on the amino group,(1-26) pyrrolidinyl lower alkoxy groups,(1-27) isoxazolyl groups,(1-28) cycloalkylcarbonyl groups,(1-29) naphthyloxy groups,(1-30) pyridyl groups,(1-31) furyl groups,(1-32) phenylthio group,(1-33) oxo group,(1-34) carbamoyl group,(1-35) 5 to 7-membered saturated heterocyclic groups containing one ortwo nitrogen atoms (preferably pyrrolidinyl, piperazinyl or piperidyl),the heterocyclic group optionally being substituted with one to threesubstituents selected from the group consisting of oxo group; loweralkyl groups; lower alkanoyl groups; phenyl lower alkyl groups; phenylgroups optionally substituted with one to three members selected fromthe group consisting of halogen atoms and lower alkoxy groups; andpyridyl groups,(1-36) oxido group and(1-37) lower alkoxido groups,with the proviso that R¹⁰¹ and R¹⁰² are not simultaneously unsubstitutedphenyl.

More preferred embodiments of the pyrrolidine compound (1) includecompounds represented by General Formula (1)

and salts thereof,wherein R¹⁰¹ is(1) a phenyl group or(3) a benzothienyl group,and each of which may have on the aromatic or heterocyclic ring one ortwo substituents selected from the group consisting of (1-1) halogenatoms and (1-3) lower alkyl groups optionally substituted with one tothree halogen atoms, and R¹⁰² is(1) a phenyl group,(2) a pyridyl group,(3) a benzothienyl group,(4) an indolyl group,(5) a 2,3-dihydro-1H-indenyl group,(6) a naphthyl group,(7) a benzofuryl group,(8) a quinolyl group,(9) a thiazolyl group,(10) a pyrimidinyl group,(11) a pyrazinyl group,(12) a benzothiazolyl group,(13) a thieno[3,2-b]pyridyl group,(14) a thienyl group,(15) a cycloalkyl group,(16) a tetrahydropyranyl group,(17) a pyrrolyl group,(18) a 2,4-dihydro-1,3-benzodioxinyl group,(19) a 2,3-dihydrobenzofuryl group,(20) a 9H-fluorenyl group,(21) a pyrazolyl group,(22) a pyridazinyl group,(23) an indolinyl group,(24) a thieno[2,3-b]pyridyl group,(25) a thieno[3,2-d]pyrimidinyl group,(26) a thieno[3,2-e]pyrimidinyl group,(27) a 1H-pyrazolo[3,4-b]pyridyl group,(28) an isoquinolyl group,(29) a 2,3-dihydro-1,4-benzoxadinyl group,(30) a quinoxalinyl group,(31) a quinazolinyl group,(32) a 1,2,3,4-tetrahydroquinolyl group,(40) a 1,3-benzodioxolyl group,(41) a 2,3-dihydro-1,4-benzodioxinyl group,(42) a 3,4-dihydro-1,5-benzodioxepinyl group,(43) a dihydropyridyl group,(44) a 1,2-dihydroquinolyl group,(45) a 1,2,3,4-tetrahydroisoquinolyl group,(46) a benzoxazolyl group,(47) a benzoisothiazolyl group,(48) an indazolyl group,(49) a benzoimidazolyl group,(50) an imidazolyl group,(59) a hydroxy-substituted lower alkyl group or(60) a lower alkoxy lower alkyl groupand each of groups (1) to (50) may have on the aromatic or heterocyclicring one to five (preferably one to three) substituents selected fromthe following (1-1) to (1-37):(1-1) halogen atoms,(1-2) lower alkylthio groups optionally substituted with one or more(preferably one to three) halogen atoms,(1-3) lower alkyl groups optionally substituted with one or more(preferably one to three) halogen atoms,(1-4) lower alkoxy groups optionally substituted with one or more(preferably one to four) halogen atoms,(1-5) nitro group,(1-6) lower alkoxycarbonyl groups,(1-7) amino groups optionally substituted with one or two lower alkylgroups,(1-8) lower alkylsulfonyl groups,(1-9) cyano group,(1-10) carboxy group,(1-11) hydroxy group,(1-12) thienyl groups,(1-13) oxazolyl groups,(1-14) naphthyl groups,(1-15) benzoyl group,(1-16) phenoxy groups optionally substituted with one to three halogenatoms on phenyl ring,(1-17) phenyl lower alkoxy groups,(1-18) lower alkanoyl groups,(1-19) phenyl groups optionally substituted on the phenyl ring with oneto five (preferably one to three) substituents selected from the groupconsisting of halogen atoms, lower alkoxy groups, cyano group, loweralkanoyl groups and lower alkyl groups,(1-20) phenyl lower alkyl groups,(1-21) cyano lower alkyl groups,(1-22) 5 to 7-membered saturated heterocyclic group-substituted sulfonylgroups, the heterocyclic group containing on the heterocyclic ring oneor two nitrogen atoms (preferably piperidylsulfonyl),(1-23) thiazolyl groups optionally substituted with one or two loweralkyl groups on the thiazole ring,(1-24) imidazolyl groups,(1-25) amino lower alkyl groups optionally substituted with one or twolower alkyl groups on the amino group,(1-26) pyrrolidinyl lower alkoxy groups,(1-27) isoxazolyl groups,(1-28) cycloalkylcarbonyl groups,(1-29) naphthyloxy groups,(1-30) pyridyl groups,(1-31) furyl groups,(1-32) phenylthio group,(1-33) oxo group,(1-34) carbamoyl group,(1-35) 5 to 7-membered saturated heterocyclic groups containing one ortwo nitrogen atoms (preferably pyrrolidinyl, piperazinyl or piperidyl),the heterocyclic group optionally being substituted with one to threesubstituents selected from the group consisting of oxo group; loweralkyl groups; lower alkanoyl groups; phenyl lower alkyl groups; phenylgroups optionally substituted with one to three-members selected fromthe group consisting of halogen atoms and lower alkoxy groups; andpyridyl groups,(1-36) oxido group and(1-37) lower alkoxido groups,with the proviso that R¹⁰¹ and R¹⁰² are not simultaneously unsubstitutedphenyl.

Particularly preferred embodiments of the pyrrolidine compound (1)include compounds represented by General Formula (1)

and salts thereof,wherein R¹⁰¹ is(1) a phenyl group substituted on the phenyl ring with one or twosubstituents selected from the group consisting of (1-1) halogen atomsand (1-3) lower alkyl groups optionally substituted with one to threehalogen atoms, and

R¹⁰² is

(1) a phenyl group,(2) a pyridyl group,(9) a thiazolyl group,(10) a pyrimidinyl group,(11) a pyrazinyl group,(14) a thienylgroup,(48) an indazolyl group,(59) a hydroxy-substituted lower alkyl group or(60) a lower alkoxy lower alkyl group,and each of the groups (1), (2), (9), (10), (11), (14) and (48) may haveon the aromatic or heterocyclic ring one or two substituents selectedfrom the group consisting of(1-1) halogen atoms,(1-3) lower alkyl groups optionally substituted with one to threehalogen atoms and(1-9) cyano group.

Examples of particularly preferable pyrrolidine compounds of the presentinvention are as follows:

-   (4-chlorophenyl)phenyl-(S)-pyrrolidin-3-ylamine,-   (4-fluorophenyl)phenyl-(S)-pyrrolidin-3-ylamine,-   (3,4-difluorophenyl)phenyl-(S)-pyrrolidin-3-ylamine,-   bis-(4-fluorophenyl)-(S)-pyrrolidin-3-ylamine,-   (3,4-difluorophenyl)-(4-fluorophenyl)-(S)-pyrrolidin-3-ylamine,-   (3-chloro-4-fluorophenyl)-(S)-pyrrolidin-3-yl-p-tolylamine,-   4-[(S)-(4-fluoro-3-methylphenyl)pyrrolidin-3-ylamino]-benzonitrile,-   bis-(3-fluorophenyl)-(S)-pyrrolidin-3-ylamine,-   (3-chloro-4-fluorophenyl)-(S)-pyrrolidin-3-ylthiazol-2-ylamine,-   (4-fluorophenyl)-(S)-pyrrolidin-3-ylthiazol-2-ylamine,-   (3,4-dichlorophenyl)-(S)-pyrrolidin-3-ylthiazol-2-ylamine,-   (3,4-dichlorophenyl)pyrimidin-5-yl-(S)-pyrrolidin-3-ylamine,-   (3-chloro-4-fluorophenyl)pyrazin-2-yl-(S)-pyrrolidin-3-ylamine,-   (3-chloro-4-fluorophenyl)-(5-chloropyridin-2-yl)-(S)-pyrrolidin-3-ylamine,-   (3-chloro-4-fluorophenyl)pyridin-2-yl-(S)-pyrrolidin-3-ylamine,-   (3-chloro-4-fluorophenyl)pyridin-3-yl-(S)-pyrrolidin-3-ylamine,-   (3-chloro-4-fluorophenyl)-(6-fluoropyridin-3-yl)-(S)-pyrrolidin-3-ylamine,-   (3,4-dichlorophenyl)pyridin-3-yl-(S)-pyrrolidin-3-ylamine,-   (3-chloro-4-fluorophenyl)-(S)-pyrrolidin-3-ylthiophen-3-ylamine,-   (3-chloro-4-fluorophenyl)-(5-fluoropyridin-3-yl)-(S)-pyrrolidin-3-ylamine,-   (4-fluoro-3-methylphenyl)-(5-fluoropyridin-3-yl)-(S)-pyrrolidin-3-ylamine,-   2-[(S)-(3-chloro-4-fluorophenyl)pyrrolidin-3-ylamino]ethanol,-   1-[(S)-(3-chloro-4-fluorophenyl)pyrrolidin-3-ylamino]-2-methyl-propan-2-ol,-   (3-chloro-4-fluorophenyl)-(2-methoxyethyl)-(S)-pyrrolidin-3-ylamine,-   3-[(S)-(3-chloro-4-fluorophenyl)pyrrolidin-3-ylamino]-propan-1-ol,-   (3-chloro-4-fluorophenyl)-(3-methoxypropyl)-(S)-pyrrolidin-3-ylamine,-   (3-chloro-4-fluorophenyl)-(1-methyl-1H-indazol-5-yl)-(S)-pyrrolidin-3-ylamine,-   benzo[b]thiophen-6-yl-(S)-pyrrolidin-3-ylthiophen-3-ylamine, and-   benzo[b]thiophen-5-yl-(S)-pyrrolidin-3-ylthiophen-3-ylamine.

Specific examples of groups in General Formula (1) are as follows.

Examples of halogen atoms include fluorine, chlorine, bromine, andiodine.

Examples of lower alkylthio groups optionally substituted with one ormore halogen atoms include straight or branched C₁₋₆ alkylthio groupsoptionally substituted with one to three halogen atoms, such asmethylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio,isobutylthio, tert-butylthio, sec-butylthio, n-pentylthio,isopentylthio, neopentylthio, n-hexylthio, isohexylthio,3-methylpenthylthio, trifluoromethylthio, trichloromethylthio,chloromethylthio, bromomethylthio, fluoromethylthio, iodomethylthio,difluoromethylthio, dibromomethylthio, 2-chloroethylthio,2,2,2-trifluoroethylthio, 2,2,2-trichloroethylthio, 3-chloropropylthio,2,3-dichloropropylthio, 4,4,4-trichlorobutylthio, 4-fluorobutylthio,5-chloropentylthio, 3-chloro-2-methylpropylthio, 5-bromohexylthio,5,6-dibromohexylthio, etc.

Examples of lower alkyl groups optionally substituted with one or morehalogen atoms include straight or branched C₁₋₆ alkyl groups optionallysubstituted with one to four halogen atoms, such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl,isopentyl, neopentyl, n-hexyl, isohexyl, 3-methylpentyl,trifluoromethyl, trichloromethyl, chloromethyl, bromomethyl,fluoromethyl, iodomethyl, difluoromethyl, dibromomethyl, 2-chloroethyl,2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 3-chloropropyl,2,3-dichloropropyl, 4,4,4-trichlorobutyl, 4-fluorobutyl, 5-chloropentyl,3-chloro-2-methylpropyl, 5-bromohexyl, 5,6-dibromohexyl,1,1,2,2-tetrafluoroethyl, etc.

Examples of lower alkoxy groups optionally substituted with one or morehalogen atoms include straight or branched C₁₋₆ alkoxy groups optionallysubstituted with one to four halogen atoms, such as methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy,n-pentyloxy, isopentyloxy, neopentyloxy, n-hexyloxy, isohexyloxy,3-methylpentyloxy, trifluoromethoxy, trichloromethoxy, chloromethoxy,bromomethoxy, fluoromethoxy, iodomethoxy, difluoromethoxy,dibromomethoxy, 2-chloroethoxy, 2,2,2-trifluoroethoxy,2,2,2-trichloroethoxy, 3-chloropropoxy, 2,3-dichloropropoxy,4,4,4-trichlorobutoxy, 4-fluorobutoxy, 5-chloropentyloxy,3-chloro-2-methylpropoxy, 5-bromohexyloxy, 5,6-dibrmohexyloxy,1,1,2,2-tetrafluoroethoxy, etc.

Examples of lower alkoxycarbonyl groups include alkoxycarbonyl groupswherein the alkoxy moiety is a straight or branched C₁₋₆ alkoxy group,such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl,isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl,tert-butoxycarbonyl, sec-butoxycarbonyl, n-pentyloxycarbonyl,neopentyloxycarbonyl, n-hexyloxycarbonyl, isohexyloxycarbonyl,3-methylpentyloxycarbonyl, etc.

Examples of lower alkyl groups include straight or branched C₁₋₆ alkylgroups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,tert-butyl, sec-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl,isohexyl, 3-methylpentyl, etc.

Examples of lower alkanoyl groups include a straight or branched C₁₋₆alkanoyl group such as formyl, acetyl, propionyl, butyryl, isobutyryl,pentanoyl, tert-butylcarbonyl, hexanoyl, etc.

Examples of lower alkylsulfonyl groups include straight or branched C₁₋₆alkyl sulfonyl groups, such as methylsulfonyl, ethylsulfonyl,n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl,tert-butylsulfonyl, sec-butylsulfonyl, n-pentylsulfonyl,isopentylsulfonyl, neopentylsulfonyl, n-hexylsulfonyl, isohexylsulfonyl,3-methylpentylsulfonyl, etc.

Examples of phenoxy groups optionally substituted with one to threehalogen atoms on the phenyl ring include phenoxy, 2-fluorophenoxy,3-fluorophenoxy, 4-fluorophenoxy, 2-chlorophenoxy, 3-chlorophenoxy,4-chlorophenoxy, 2-bromophenoxy, 3-bromophenoxy, 4-bromophenoxy,2-iodophenoxy, 3-iodophenoxy, 4-iodophenoxy, 2,3-difluorophenoxy,3,4-difluorophenoxy, 3,5-difluorophenoxy, 2,4-difluorophenoxy,2,6-difluorophenoxy, 2,3-dichlorophenoxy, 3,4-dichlorophenoxy,3,5-dichlorophenoxy, 2,4-dichlorophenoxy, 2,6-dichlorophenoxy,3,4,5-trifluorophenoxy, 3,4,5-trichlorophenoxy, 2,4,6-trifluorophenoxy,2,4,6-trichlorophenoxy, 2-fluoro-4-bromophenoxy,4-chloro-3-fluorophenoxy, 2,3,4-trichlorophenoxy, etc.

Examples of phenyl lower alkoxy groups include phenylalkoxy groupswherein the alkoxy moiety is a straight or branched C₁₋₆ alkoxy group,such as benzyloxy, 2-phenylethoxy, 1-phenylethoxy, 3-phenylpropoxy,4-phenylbutoxy, 5-phenylpentyloxy, 6-phenylhexyloxy,1,1-dimethyl-2-phenylethoxy, 2-methyl-3-phenylpropoxy, etc.

Examples of phenyl lower alkyl groups include phenylalkyl groups whereinthe alkyl moiety is a straight or branched C₁₋₆ alkyl group, such asbenzyl, 1-phenethyl, 2-phenethyl, 3-phenylpropyl, 2-phenylpropyl,4-phenylbutyl, 5-phenylpentyl, 4-phenylpentyl, 6-phenylhexyl,2-methyl-3-phenylpropyl, 1,1-dimethyl-2-phenylethyl, etc.

Examples of cyano lower alkyl groups include cyanoalkyl groups whereinthe alkyl moiety is a straight or branched C₁₋₆ alkyl group, such ascyanomethyl, 2-cyanoethyl, 1-cyanoethyl, 3-cyanopropyl, 4-cyanobutyl,1,1-dimethyl-2-cyanoethyl, 5-cyanopentyl, 6-cyanohexyl,1-cyanoisopropyl, 2-methyl-3-cyanopropyl, etc.

Examples of thiazolyl groups optionally substituted with one or twolower alkyl groups on the thiazole ring include thiazolyl groupsoptionally substituted with one or two straight or branched C₁₋₆ alkylgroups on the thiazole ring, such as (2-, 4-, or 5-)thiazolyl,2-methyl-(4-, or 5-)thiazolyl, 4-methyl-(2- or 5-)thiazolyl, 2-ethyl-(4-or 5-)thiazolyl, 4-n-propyl-(2- or 5-)thiazolyl, 5-n-butyl-(2- or4-)thiazolyl, 2-n-pentyl-(4- or 5-)thiazolyl, 4-n-hexyl-(2- or5-)thiazolyl, 2,4-dimethyl-5-thiazolyl, etc.

Examples of amino lower alkyl groups optionally substituted with one ortwo lower alkyl groups on an amino group include aminoalkyl groupswherein the alkyl moiety is a straight or branched C₁₋₆ alkyl group andwhich are optionally substituted on an amino group with one or twostraight or branched C₁₋₆ alkyl groups; such as aminomethyl,2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl,6-aminohexyl, 1,1-dimethyl-2-aminoethyl, 2-methyl-3-aminopropyl,methylaminomethyl, 2-ethylaminoethyl, 3-propylaminopropyl,3-isopropylaminopropyl, 4-butylaminobutyl, 5-pentylaminopentyl,6-hexylaminohexyl, 2-dimethylaminoethyl, 2-diisopropylaminopropyl,3-dimethylaminopropyl, diisopropylaminomethyl, 3-diisopropylaminopropyl,(N-ethyl-N-propylamino)methyl, 2-(N-methyl-N-hexylamino)methyl, etc.

Examples of pyrrolidinyl lower alkoxy groups include pyrrolidinyl alkoxygroups wherein the alkoxy moiety is a straight or branched C₁₋₆ alkoxygroup, such as (1-, 2-, or 3-)pyrrolydinyl methoxy, 2-[(1-, 2-, or3-)pyrrolydinyl]ethoxy, 1-[(1-, 2-, or 3-)pyrrolydinyl]ethoxy, 3-[(1-,2-, or 3-)pyrrolydinyl)propoxy, 4-[(1-, 2-, or 3-)pyrrolydinyl]butoxy,5-[(1-, 2-, or 3-)pyrrolydinyl]pentyloxy, 6-[(1-, 2-, or3-)pyrrolydinyl]hexyloxy, 1,1-dimethyl-2-((1-, 2-, or3-)pyrrolydinyl]ethoxy, 2-methyl-3-[(1-, 2-, or 3-)pyrrolydinyl]propoxy, etc.

Examples of cycloalkyl groups include C₃₋₈ cycloalkyl groups, such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, etc.

Examples of cycloalkylcarbonyl groups include cycloalkylcarbonyl groupswherein the cycloalkyl moiety is a C₃₋₈ cycloalkyl group, such ascyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl,cyclohexylcarbonyl, cycloheptylcarbonyl, cyclooctylcarbonyl, etc.

Examples of lower alkoxy groups include straight or branched C₁₋₆ alkoxygroups, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, tert-butoxy, sec-butoxy, n-pentyloxy, isopentyloxy,neopentyloxy, n-hexyloxy, isohexyloxy, 3-methylpentyloxy, etc.

Examples of lower alkylthio groups include straight or branched C₁₋₆alkylthio groups such as methylthio, ethylthio, n-propylthio,isopropylthio, n-butylthio, isobutylthio, tert-butylthio, sec-butylthio,n-pentylthio, isopentylthio, neopentylthio, n-hexylthio, isohexylthio,3-methylpentylthio, etc.

Examples of phenyl groups optionally substituted on the phenyl ring withone to three members selected from the group consisting of halogen atomsand lower alkoxy groups include phenyl groups optionally substituted onthe phenyl ring with one to three members selected from the groupconsisting of halogen atoms and straight or branched C₁₋₆ alkoxy groups,such as phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxylphenyl,2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 4-isopropoxyphenyl,3-butoxyphenyl, 4-pentyloxyphenyl, 4-hexyloxyphenyl,3,4-dimethoxyphenyl, 3,4-diethoxyphenyl, 2,4-dimethoxyphenyl,2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,4,5-trimethoxyphenyl,2-methoxy-4-fluorophenyl, 4-fluorophenyl, 2,5-difluorophenyl,2,4-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl,2,6-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl,3,4-dichlorophenyl, 2,6-dichlorophenyl, 3-fluorophenyl, 2-fluorophenyl,3-bromophenyl, 4-iodophenyl, 2-bromophenyl, 4-bromophenyl,3,5-dichlorophenyl, 2,4,6-trifluorophenyl, 2-chlorophenyl,3-chlorophenyl, 4-chlorophenyl, 2-iodophenyl, 3-iodophenyl,2,3-dibromophenyl, 2,4-diiodophenyl, 2,4,6-trichlorophenyl, etc.

Examples of 5- to 7-membered saturated heterocyclic groups containing onthe heterocyclic ring one or two heteroatoms selected from the groupconsisting of nitrogen, oxygen and sulfur include pyrrolidinyl,piperazinyl, piperidinyl, morpholino, thiomorpholino, homopiperazinyl,homopiperidinyl, imidazolidinyl, thiazolidinyl, isothiazolidinyl,oxazolidinyl, isoxazolidinyl, isothiazolidinyl and pyrazolidinyl.

Examples of the above-mentioned heterocyclic groups substituted with oneto three members selected from the group consisting of oxo group; loweralkyl groups; lower alkanoyl groups; phenyl lower alkyl groups; phenylgroups optionally substituted on the phenyl ring with one to threemembers selected from the group consisting of halogen atoms and loweralkoxy groups; and pyridyl groups:

include the above-mentioned heterocyclic groups substituted with one tothree members selected from the group consisting of oxo groups; straightor branched C₁₋₆ alkyl groups; straight or branched C₁₋₆ alkanoylgroups; phenyl alkyl groups wherein the alkyl moiety is a straight orbranched C₁₋₆ alkyl group; phenyl groups optionally substituted on thephenyl ring with one to three members selected from the group consistingof halogen atoms and straight or branched C₁₋₆ alkoxy groups; andpyridyl groups;

such as 2-oxo-(1-, 3-, 4-, or 5-)pyrrolidinyl, 2-oxo-(1-, 3-, 4-, 5-, or6-)piperazinyl, 4-methyl-(1-, 2-, or 3-)piperazinyl, 4-acetyl-(1-, 2-,or 3-)piperazinyl, 4-ethyl-(1-, 2-, or 3-)piperazinyl, 2-methyl-(l-, 2-,3-, 4-, or 5-)pyrrolidinyl, 2-methyl-(1-, 2-, 3-, 4-, 5-, or6-)piperidinyl, 2,4-dimethyl-(1-, 2-, 3-, 5-, or 6-)piperidinyl,3-methyl-(1-, 2-, 3-, 4-, or 5-)pyrrolidinyl, 2,3,4-trimethyl-(1-, 2-,3-, 5-, or 6-)piperazinyl, 4-acetyl-3-methyl-(1-, 2-, 3-, 5-, or6-)piperazinyl, 3-methyl-(2-, 3-, 4-, 5-, or 6-)morpholino,2-acetyl-(2-, 3-, 4-, 5-, or 6-)morpholino, 4-(2-phenylethyl)-(1-, 2-,or 3-)piperazinyl, 4-(3,4-dichlorophenyl)-(1-, 2-, 3-, or4-)piperazinyl, 4-(4-methoxyphenyl)-(l-, 2-, or 3-)piperazinyl,4-(2-chlorophenyl)-(1-, 2-, or 3-)piperazinyl, 4-[(2-, 3-, or 4-)pyridyl]-(1-, 2-, or 3-)piperazinyl, 4-phenyl-(1-, 2-, or3-)piperazinyl, 4-benzyl-(1-, 2-, or 3-)piperidinyl,4-(3,4-dichlorophenyl)-(1-, 2-, or 3-)morpholino,2-(4-methoxyphenyl)-(1-, 2-, 3-, 4-, or 5-)pyrrolidinyl,4-(2-chlorophenyl)-(1-, 2-, or 3-)piperidinyl, 4-[(2-, 3-, or 4-)pyridyl]-(l-, 2-, or 3-)piperidinyl, 4-phenyl-(1-, 2-, or 3-)piperidinyl, 4-phenyl-3-methyl-(1-, 2-, 3-, 5-, or 6-) piperazinyl,4-[(2-, 3-, or 4-)pyridyl]-2-acetyl-(1-, 2-, 3-, 5-, or 6-)piperazinyl,etc.

Examples of cycloalkyl lower alkyl groups include cycloalkyl alkylgroups wherein the cycloalkyl moiety is a C₃₋₈ cycloalkyl group and thealkyl moiety is a straight or branched C₁₋₆ alkyl group, such ascyclopropylmethyl, cyclohexylmethyl, 2-cyclopropylethyl,1-cyclobutylethyl, cyclopentylmethyl, 3-cyclopentylpropyl,4-cyclohexylbutyl, 5-cycloheptylpentyl, 6-cyclooctylhexyl,1,1-dimethyl-2-cyclohexylethyl, 2-methyl-3-cyclopropylpropyl, etc.

Examples of lower alkylthio lower alkyl groups include alkylthioalkylgroups wherein the alkylthio moiety is a straight or branched C₁₋₆alkylthio group and the alkyl moiety is a straight or branched C₁₋₆alkyl group, such as methylthiomethyl, 2-methylthioethyl,1-ethylthioethyl, 2-ethylthioethyl, 3-n-butylthiopropyl,4-n-propylthiobutyl, 1,1-dimethyl-2-n-pentylthioethyl,5-n-hexylthiopentyl, 6-methylthiohexyl, 1-ethylthioisopropyl,2-methyl-3-methylthiopropyl, etc.

Examples of phenoxy lower alkyl groups include phenoxy alkyl groupswherein the alkyl moiety is a straight or branched C₁₋₆ alkyl group,such as phenoxymethyl, 1-phenoxyethyl, 2-phenoxyethyl, 3-phenoxypropyl,2-phenoxypropyl, 4-phenoxybutyl, 5-phenoxypentyl, 4-phenoxypentyl,6-phenoxyhexyl, 2-methyl-3-phenoxypropyl, 1,1-dimethyl-2-phenoxyethyl,etc.

Examples of pyridyloxy lower alkyl groups include pyridyloxyalkyl groupswherein the alkyl moiety is a straight or branched C₁₋₆ alkyl group,such as [2-, 3-, or 4-]pyridyloxy]methyl, 1-[2-, 3-, or4-]pyridyloxy]ethyl, 2-[2-, 3-, or 4-]pyridyloxy]ethyl, 3-[2-, 3-, or4-]pyridyloxy]propyl, 2-[2-, 3-, or 4-]pyridyloxy]propyl, 4-(2-, 3-, or4-]pyridyloxy]butyl, 5-[2-, 3-, or 4-]pyridyloxy]pentyl, 4-[2-, 3-, or4-]pyridyloxy]pentyl, 6-[2-, 3-, or 4-]pyridyloxy]hexyl, 2-methyl-3-[2-,3-, or 4-]pyridyloxy]propyl, 1,1-dimethyl-2-[2-, 3-, or4-]pyridyloxy]ethyl, etc.

Examples of lower alkynyl groups include C₂₋₆ straight or branchedalkynyl groups, such as ethynyl, (1- or 2-) propynyl, 1-methyl-(1- or2-)propynyl, 1-ethyl-(1- or 2-)propynyl, (1-, 2- or 3-)butynyl and (1-,2-, 3- or 4-)pentynyl, (1-, 2-, 3-, 4- or 5-)hexynyl, etc.

Examples of phenyl lower alkenyl groups include phenylalkenyl groupscontaining one to three double bonds wherein the alkenyl moiety is astraight or branched C₂₋₆ alkenyl group, such as styryl,3-phenyl-2-propenyl (trivial name: cinnamyl), 4-phenyl-2-butenyl,4-phenyl-3-butenyl, 5-phenyl-4-pentenyl, 5-phenyl-3-pentenyl,6-phenyl-5-hexenyl, 6-phenyl-4-hexenyl, 6-phenyl-3-hexenyl,4-phenyl-1,3-butadienyl, 6-phenyl-1,3,5-hexatrienyl, etc.

Examples of cycloalkyl lower alkyl groups include cycloalkyl alkylgroups wherein the cycloalkyl moiety is a C₃₋₈ cycloalkyl group asdefined above and the alkyl moiety is a straight or branched C₁₋₆ alkylgroup as defined above.

Examples of lower alkylthio lower alkyl groups include alkylthio alkylgroups wherein the alkylthio moiety is a straight or branched C₁₋₆alkylthio group as defined above and the alkyl moiety is a straight orbranched C₁₋₄ alkyl group as defined above.

Examples of amino-substituted lower alkyl groups optionally substitutedwith one or two lower alkyl groups on the amino group includeamino-substituted alkyl groups optionally substituted with one or twostraight or branched C₁₋₆ alkyl groups on the amino group wherein thealkyl moiety is a straight or branched C₁₋₆ alkyl group as definedabove.

Examples of phenoxy lower alkyl groups include phenoxy alkyl groupswherein the alkyl moiety is a straight or branched C₁₋₆ alkyl group asdefined above.

Examples of pyridyloxy lower alkyl groups include pyridyloxy alkylgroups wherein the alkyl moiety is a straight or branched C₁₋₆ alkylgroup as defined above.

Examples of 1,2,3,4-tetrahydronaphthyl lower alkyl groups include1,2,3,4-tetrahydronaphthyl alkyl groups wherein the alkyl moiety is astraight or branched C₁₋₆ alkyl group as defined above.

Examples of imidazo[1,2-a]pyridyl lower alkyl groups includeimidazo[1,2-a]pyridyl alkyl groups wherein the alkyl moiety is astraight or branched C₁₋₆ alkyl group as defined above.

Examples of thiazolyl lower alkyl groups include thiazolyl alkyl groupswherein the alkyl moiety is a straight or branched C₁₋₆ alkyl group asdefined above.

Examples of tetrahydropyranyl lower alkyl groups includetetrahydropyranyl alkyl groups wherein the alkyl moiety is a straight orbranched C₁₋₆ alkyl group as defined above.

Examples of piperidyl lower alkyl groups include piperidyl alkyl groupswherein the alkyl moiety is a straight or branched C₁₋₆ alkyl group asdefined above.

Examples of diphenyl lower alkoxy-substituted lower alkyl groups includediphenyl alkoxy-substituted alkyl groups wherein the alkoxy moiety is astraight or branched C₁₋₆ alkoxy group as defined above and the alkylmoiety is a straight or branched C₁₋₆ alkyl group as defined above.

Examples of lower alkoxycarbonyl-substituted lower alkyl groups includealkoxycarbonyl-substituted alkyl groups wherein the alkoxy moiety is astraight or branched C₁₋₆ alkoxy group as defined above and the alkylmoiety is a straight or branched C₁₋₆ alkyl group as defined above.

Examples of phenyl lower alkoxycarbonyl-substituted lower alkyl groupsinclude phenyl alkoxycarbonyl-substituted alkyl groups wherein thealkoxy moiety is a straight or branched C₁₋₆ alkoxy group as definedabove and the alkyl moiety is a straight or branched C₁₋₆ alkyl group asdefined above.

Examples of hydroxy-substituted lower alkyl groups includehydroxy-substituted alkyl groups wherein the alkyl moiety is a straightor branched C₁₋₆ alkyl group as defined above having 1 to 3 hydroxygroups, such as hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl,2,3-dihydroxypropyl, 3-hydroxypropyl, 2-hydroxypropyl, 4-hydroxybutyl,3,4-dihydroxybutyl, 5-hydroxypentyl, 4-hydroxypentyl, 6-hydroxyhexyl,2,2-dimethyl-3-hydroxypropyl, 1,1-dimethyl-2-hydroxyethyl,2,3,4-trihydroxybutyl, etc.

Examples of lower alkoxy lower alkyl groups include alkoxy alkyl groupswherein the alkoxy moiety is a straight or branched C₁₋₆ alkoxy group asdefined above and the alkyl moiety is a straight or branched C₁₋₆ alkylgroup as defined above, such as methoxymethyl, 1-methoxyethyl,2-methoxyethyl, 2-ethoxypropyl, 3-methoxypropyl, 3-ethoxypropyl,3-propoxypropyl, 4-methoxybutyl, 3-methoxybutyl, 5-methoxypentyl,4-ethoxypentyl, 6-methoxyhexyl, 2,2-dimethyl-3-methoxypropyl,1,1-dimethyl-2-methoxyethyl etc.

Examples of carboxy lower alkyl groups include carboxy alkyl groupswherein the alkyl moiety is a straight or branched C₁₋₆ alkyl group asdefined above.

Examples of carbamoyl-substituted lower alkyl groups optionallysubstituted with one or two lower alkyl groups on the carbamoyl groupinclude carbamoyl-substituted alkyl groups optionally substituted withone or two straight or branched C₁₋₆ alkyl groups on the carbamoyl groupwherein the alkyl moiety is a straight or branched C₁₋₆ alkyl group asdefined above.

Examples of morpholinylcarbonyl lower alkyl groups includemorpholinylcarbonyl alkyl groups wherein the alkyl moiety is a straightor branched C₁₋₆ alkyl group as defined above.

Examples of benzoyl lower alkyl groups include benzoyl alkyl groupswherein the alkyl moiety is a straight or branched C₁₋₆ alkyl group asdefined above.

Examples of phenylthio lower alkyl groups include phenylthio alkylgroups wherein the alkyl moiety is a straight or branched C₁₋₆ alkylgroup as defined above.

Examples of naphthylthio lower alkyl groups include naphthylthio alkylgroups wherein the alkyl moiety is a straight or branched C₁₋₆ alkylgroup as defined above.

Examples of cycloalkylthio lower alkyl groups include cycloalkylthioalkyl groups wherein the alkyl moiety is a straight or branched C₁₋₆alkyl group as defined above.

Examples of pyridylthio lower alkyl groups include pyridylthio alkylgroups wherein the alkyl moiety is a straight or branched C₁₋₆ alkylgroup as defined above.

Examples of pyrimidinylthio lower alkyl groups include pyrimidinylthioalkyl groups wherein the alkyl moiety is a straight or branched C₁₋₆alkyl group as defined above.

Examples of furylthio lower alkyl groups include furylthio alkyl groupswherein the alkyl moiety is a straight or branched C₁₋₆ alkyl group asdefined above.

Examples of thienylthio lower alkyl groups include thienylthio alkylgroups wherein the alkyl moiety is a straight or branched C₁₋₆ alkylgroup as defined above.

Examples of 1,3,4-thiadiazolylthio lower alkyl groups include1,3,4-thiadiazolylthio alkyl groups wherein the alkyl moiety is astraight or branched C₁₋₆ alkyl group as defined above.

Examples of benzimidazolylthio lower alkyl groups includebenzimidazolylthio alkyl groups wherein the alkyl moiety is a straightor branched C₁₋₆ alkyl group as defined above.

Examples of benzthiazolylthio lower alkyl groups includebenzthiazolylthio alkyl groups wherein the alkyl moiety is a straight orbranched C₁₋₆ alkyl group as defined above.

Examples of tetrazolylthio lower alkyl groups include tetrazolylthioalkyl groups wherein the alkyl moiety is a straight or branched C₁₋₆alkyl group as defined above.

Examples of benzoxazolylthio lower alkyl groups include benzoxazolylthioalkyl groups wherein the alkyl moiety is a straight or branched C₁₋₆alkyl group as defined above.

Examples of thiazolylthio lower alkyl groups include thiazolylthio alkylgroups wherein the alkyl moiety is a straight or branched C₁₋₆ alkylgroup as defined above.

Examples of imidazolylthio lower alkyl groups include imidazolylthioalkyl groups wherein the alkyl moiety is a straight or branched C₁₋₆alkyl group as defined above.

Examples of amino-substituted lower alkylthio lower alkyl groupsoptionally substituted with one or two lower alkyl groups on the aminogroup include amino-substituted alkylthio alkyl groups optionallysubstituted with one or two straight or branched C₁₋₆ alkyl groups onthe amino group wherein the alkylthio moiety is a straight or branchedC₁₋₆ alkylthio group as defined above and the alkyl moiety is a straightor branched C₁₋₆ alkyl group as defined above.

Examples of phenyl-substituted lower alkylthio lower alkyl groupsinclude phenyl-substituted alkylthio alkyl groups wherein the alkylthiomoiety is a straight or branched C₁₋₆ alkylthio group as defined aboveand the alkyl moiety is a straight or branched C₁₋₆ alkyl group asdefined above.

Examples of furyl-substituted lower alkylthio lower alkyl groups includefuryl-substituted alkylthio alkyl groups wherein the alkylthio moiety isa straight or branched C₁₋₆ alkylthio group as defined above and thealkyl moiety is a straight or branched C₁₋₆ alkyl group as definedabove.

Examples of pyridyl-substituted lower alkylthio lower alkyl groupsinclude pyridyl-substituted alkylthio alkyl groups wherein the alkylthiomoiety is a straight or branched C₁₋₆ alkylthio group as defined aboveand the alkyl moiety is a straight or branched C₁₋₆ alkyl group asdefined above.

Examples of hydroxy-substituted lower alkylthio lower alkyl groupsinclude hydroxy-substituted alkylthio alkyl groups wherein the alkylthiomoiety is a straight or branched C₁₋₆ alkylthio group as defined aboveand the alkyl moiety is a straight or branched C₁₋₆ alkyl group asdefined above.

Examples of phenoxy-substituted lower alkylthio lower alkyl groupsinclude phenoxy-substituted alkylthio alkyl groups wherein the alkylthiomoiety is a straight or branched C₁₋₆ alkylthio group as defined aboveand the alkyl moiety is a straight or branched C₁₋₆ alkyl group asdefined above.

Examples of lower alkoxycarbonyl-substituted lower alkylthio lower alkylgroups include alkoxycarbonyl-substituted alkylthio alkyl groups whereinthe alkoxy moiety is a straight or branched C₁₋₆ alkoxy group as definedabove, the alkylthio moiety is a straight or branched C₁₋₆ alkylthiogroup as defined above and the alkyl moiety is a straight or branchedC₁₋₆ alkyl group as defined above.

Examples of lower alkenyl groups include straight or branched C₂₋₆alkenyl groups, such as vinyl, 1-propenyl, allyl, 1-methylallyl, (1-, 2-or 3-)butenyl, (1-, 2-, 3- or 4-) pentenyl and (1-, 2-, 3-, 4- or5-)hexenyl.

Examples of dihydropyridyl groups include 1,2-dihydropyridyl,3,4-dihydropyridyl and the like.

Examples of 5- to 7-membered saturated heterocyclic group-substitutedsulfonyl groups, the heterocyclic group containing one or twoheteroatoms selected from the group consisting of nitrogen, oxygen andsulfur, include pyrrolidinyl-sulfonyl, piperazinylsulfonyl,piperidinylsulfonyl, morpholino-sulfonyl, thiomorpholinosulfonyl,homopiperazinylsulfonyl, homopiperidinylsulfonyl,imidazolidinylsulfonyl, thiazolidinyl-sulfonyl,isothiazolidinylsulfonyl, oxazolidinylsulfonyl, isoxazolidinylsulfonyl,isothiazolidinylsulfonyl, pyrazolidinyl-sulfonyl, etc.

Examples of lower alkoxido groups include straight or branched C₁₋₆alkoxido groups, such as methoxido, ethoxido, etc.

The pyrrolidine compounds represented by General Formula (1) can beproduced by various methods, and for example, by a method according tothe following Reaction Scheme 1.

wherein R¹⁰¹ and R¹⁰² are as defined above, and R¹¹² is anamino-protecting group.

The pyrrolidine compound (1) can be prepared by subjecting a compound(2) to an elimination reaction to remove the amino-protecting group.

Examples of amino-protecting groups usable herein include loweralkoxycarbonyl groups, lower alkanoyl groups, aryloxy carbonyl groups,aryl-substituted lower alkyl groups, etc.

Examples of lower alkoxycarbonyl groups include straight or branchedC₁₋₆ alkoxycarbonyl groups, such as methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl,hexyloxycarbonyl, etc.

Examples of lower alkanoyl groups include straight or branched C₁₋₆alkanoyl groups, such as formyl, acetyl, propionyl, butyryl, isobutyryl,pentanoyl, tert-butylcarbonyl, hexanoyl, etc.

Examples of aryloxycarbonyl groups include phenoxy carbonyl groupsoptionally substituted with one to three substituents; naphthyloxycarbonyl groups optionally substituted with one to three substituents;etc. Examples of substituents for aryl groups include methyl, ethyl,propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl,hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl,2,3-dihydroxypropyl, 4-hydroxybutyl, 1,1-dimethyl-2-hydroxyethyl,5,5,4-trihydroxypentyl, 5-hydroxypentyl, 6-hydroxyhexyl,1-hydroxyisopropyl, 2-methyl-3-hydroxypropyl, trifluormethyl,trichloromethyl, chloromethyl, bromomethyl, fluoromethyl, iodomethyl,difluoromethyl, dibromomethyl, 2-cloroethyl, 2,2,2-trifluoroethyl,2,2,2-trichloroethyl, 3-chloropropyl, 2,3-dichloropropyl,4,4,4-trichlorobutyl, 4-fluorobutyl, 5-chloropentyl,3-chloro-2-methylpropyl, 5-bromohexyl, 5,6-dichlorohexyl,3-hydroxy-2-chloropropyl, or like straight or branched C₁₋₆ alkyl groupsoptionally substituted with one to three members selected from the groupconsisting of halogen atoms and a hydroxyl group; methoxy, ethoxy,propoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy,hydroxymethoxy, 2-hydroxyethoxy, 1-hydroxyethoxy, 3-hydroxypropoxy,2,3-dihydroxypropoxy, 4-hydroxybutoxy, 1,1-dimethyl-2-hydroxyethoxy,5,5,4-trihydroxypentyloxy, 5-hydroxypentyloxy, 6-hydroxyhexyloxy,1-hydroxyisopropoxy, 2-methyl-3-hydroxypropoxy, trifluoromethoxy,trichloromethoxy, chloromethoxy, bromomethoxy, fluoromethoxy,iodomethoxy, difluoromethoxy, dibromomethoxy, 2-chloroethoxy,2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, 3-chloropropoxy,2,3-dichloropropoxy, 4,4,4-trichlorobutoxy, 4-fluorobutoxy,5-chloropentyloxy, 3-chloro-2-methylpropoxy, 5-bromohexyloxy,5,6-dichlorohexyloxy, 3-hydroxy-2-chloropropoxy, or like straight orbranched C₁₋₆ alkoxy groups optionally substituted with one to threemembers selected from the group consisting of halogen atoms and ahydroxyl group; halogen atoms such as fluorine, bromine, chlorine, andiodine; etc. When two or more substituents are present, the substituentsmay be the same or different.

Examples of aryl-substituted lower alkyl groups include benzyl,2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl,5-phenylpentyl, 6-phenylhexyl, 1,1-dimethyl-2-phenylethyl,2-methyl-3-phenylpropyl, α-naphthylmethyl, β-naphthylmethyl,2-(α-naphthyl)ethyl, 1-(β-naphthyl)ethyl, 3-(α-naphthyl)propyl,4-(β-naphthyl)butyl, 5-(α-naphthyl)pentyl, 6-(β-naphthyl)hexyl,1,1-dimethyl-2-(α-naphthyl)ethyl, 2-methyl-3-(β-naphthyl)propyl, likephenyl-substituted straight or branched C₁₋₆ alkyl groups optionallysubstituted with one to three substituents; or like naphtyl-substitutedstraight or branched C₁₋₆ alkyl groups optionally substituted with oneto three substituents. Examples of substituents for aryl groups includemethyl, ethyl, propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl,n-hexyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl,2,3-dihydroxypropyl, 4-hydroxybutyl, 1,1-dimethyl-2-hydroxyethyl,5,5,4-trihydroxypentyl, 5-hydroxypentyl, 6-hydroxyhexyl,1-hydroxyisopropyl, 2-methyl-3-hydroxypropyl, trifluoromethyl,trichloromethyl, chloromethyl, bromomethyl, fluoromethyl, iodomethyl,difluoromethyl, dibromomethyl, 2-chloroethyl, 2,2,2-trifluoroethyl,2,2,2-trichloroethyl, 3-chloropropyl, 2,3-dichloropropyl,4,4,4-trichlorobutyl, 4-fluorobutyl, 5-chloropentyl,3-chloro-2-methylpropyl, 5-bromohexyl, 5,6-dichlorohexyl,3-hydroxy-2-chloropropyl, or like straight or branched C₁₋₆ alkyl groupsoptionally substituted with one to three members selected from the groupconsisting of halogen atoms and a hydroxyl group; methoxy, ethoxy,propoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy,hydroxymethoxy, 2-hydroxyethoxy, 1-hydroxyethoxy, 3-hydroxypropoxy,2,3-dihydroxypropoxy, 4-hydroxybutoxy, 1,1-dimethyl-2-hydroxyethoxy,5,5,4-trihydroxypentyloxy, 5-hydroxypentyloxy, 6-hydroxyhexyloxy,1-hydroxyisopropoxy, 2-methyl-3-hydroxypropoxy, trifluoromethoxy,trichloromethoxy, chloromethoxy, bromomethoxy, fluoromethoxy,iodomethoxy, difluoromethoxy, dibromomethoxy, 2-chloroethoxy,2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, 3-chloropropoxy,2,3-dichloropropoxy, 4,4,4-trichlorobutoxy, 4-fluorobutoxy,5-chloropentyloxy, 3-chloro-2-methylpropoxy, 5-bromohexyloxy,5,6-dichlorohexyloxy, 3-hydroxy-2-chloropropoxy, or like straight orbranched C₁₋₆ alkoxy groups optionally substituted with one to threemembers selected from the group consisting of halogen atoms and ahydroxyl group; halogen atoms such as fluorine, bromine, chlorine, andiodine; etc. When two or more substituents are present, the substituentsmay be the same or different.

The reaction for producing compound (1) from compound (2) is carried outin a suitable solvent or without solvent in the presence of an acid orbasic compound. This reaction is referred to as “Reaction A”hereinafter.

Examples of useful solvents include water; lower alcohols such asmethanol, ethanol, isopropanol and tert-butanol; ketones such as acetoneand methyl ethyl ketone; ethers such as diethyl ether, dioxane,tetrahydrofuran, monoglyme and diglyme; aliphatic acids such as aceticacid and formic acid; esters such as methyl acetate and ethyl acetate;halogenated hydrocarbons such as chloroform, dichloromethane,dichloroethane and carbon tetrachloride; amides such asN,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrolidone;dimethyl sulfoxide; hexamethylphosphoric triamide; and mixtures of suchsolvents.

Examples of useful acids include mineral acids such as hydrochloricacid, sulfuric acid and hydrobromic acid; and organic acids such asformic acid, acetic acid, trifluoroacetic acid and p-toluenesulfonicacid.

Examples of useful basic compounds include carbonates such as sodiumcarbonate, potassium carbonate, sodium hydrogencarbonate and potassiumhydrogencarbonate; and metal hydroxides such as sodium hydroxide,potassium hydroxide, calcium hydroxide and lithium hydroxide.

An acid or basic compound is usually used in an amount of at least about1 mole, and preferably about 1 to about 10 moles, per mole of compound(2). However, an acid may also be used in a large excess relative tocompound (2).

The reaction advantageously proceeds usually at about 0 to about 200°C., and preferably at about 0 to about 150° C., and usually finishes inabout 10 minutes to about 30 hours.

When R¹¹² of compound (2) is an aryl-substituted lower alkyl group, itis also possible to produce compound (1) by the reduction of suchcompound (2).

The reduction reaction can be carried out, for example, by catalytichydrogenation in a suitable solvent in the presence of a catalyst.

Examples of useful solvents include water; acetic acid; alcohols such asmethanol, ethanol and isopropanol; hydrocarbons such as n-hexane andcyclohexane; ethers such as dioxane, tetrahydrofuran, diethyl ether andethylene glycol dimethyl ether; esters such as ethyl acetate and methylacetate; aprotic polar solvents such as dimethylformamide; and mixturesof such solvents.

Examples of useful catalysts include palladium, palladium black,palladium carbon, platinum, platinum oxide, copper chromite, Raneynickel and mixtures thereof. A catalyst is preferably used in an amountof about 0.02 to about 1 times by weight of compound (2).

The reaction temperature for the reduction reaction is usually about −20to about 100° C., and preferably about 0 to about 80° C., and thehydrogen pressure is usually from 1 to 10 atm. The reaction usuallyfinishes in about 0.5 to about 20 hours.

When R¹¹² of compound (2) is an aryl-substituted lower alkyl group,compound (2) can be reacted to form compound (1) by steps of (i)treating compound (2) with a dealkylating agent in a suitable solvent;and (ii) heating the resulting compound in a suitable solvent.

The solvent for use in the reaction of step (i) may be the same as anysolvent used for reaction (A).

Examples of useful dealkylating agents include formic esters such as1-chloroethyl chloroformate, ethyl chloroformate and tert-butylchloroformate. A dealkylating agent is usually used in an amount of atleast about 1 mole of compound (2), and preferably about 1 mole to about10 moles, per mole of compound (2).

The reaction advantageously proceeds usually at about 0 to about 150°C., and preferably at room temperature to about 100° C., and usuallycompletes in about 1 to about 25 hours.

Examples of solvents for use in step (ii) include alcohols such asmethanol, ethanol and isopropanol. Heating is conducted usually at about0 to about 150° C., and preferably at room temperature to about 100° C.for about 1 to about 10 hours.

The compound of General Formula (2) used as a starting material can beeasily produced, for example, by the process shown by Reaction Scheme 2:

wherein R¹⁰¹, R¹⁰² and R¹¹² are the same as above.

The reaction of compound (3) with compound (4) is carried out, forexample, without solvent or in a suitable solvent in the presence of areducing agent.

For the reaction, compound (4) is usually used in an amount of at leastabout 1 mole per mole of compound (3), and preferably equivalent to alarge excess relative to compound (3).

Examples of useful solvents include water; lower alcohols such asmethanol, ethanol, isopropanol, butanol, tert-butanol and ethyleneglycol; acetonitrile; aliphatic acids such as formic acid and aceticacid; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglymeand diglyme; aromatic hydrocarbons such as benzene, toluene and xylene;halogenated hydrocarbons such as dichloromethane, dichloroethane andcarbon tetrachloride; and mixtures of such solvents.

Examples of reducing agents include aliphatic acids such as formic acid;aliphatic acid alkali metal salts such as sodium formate; hydridereducing agents such as sodium boronhydride, sodium cyanoborohydride,sodium triacetoxyborohydride, aluminium lithium hydride or mixtures ofsuch hydride reducing agents; catalytic hydrogenation reducing agentssuch as palladium black, palladium carbon, platinum oxide, platinumblack and Raney nickel.

When an aliphatic acid or aliphatic acid alkali metal salt is used as areducing agent, a suitable temperature is usually from room temperatureto about 200° C., and preferably from about 50 to about 150° C. Thereaction usually completes in about 10 minutes to about 10 hours. Thealiphatic acid or aliphatic acid alkali metal salt is preferably used ina large excess relative to compound (3).

When a hydride reducing agent is used as a reducing agent, a suitablereaction temperature is usually from about −80 to about 100° C., andpreferably about −80 to about 70° C. The reaction usually finishes inabout 30 minutes to about 60 hours. The hydride reducing agent isusually used in an amount of about 1 to about 20 moles per mole ofcompound (3), and preferably about 1 to about 6 moles per mole ofcompound (3). Especially when aluminium lithium hydride is used as ahydride reducing agent, it is preferable to use ethers, such as diethylether, tetrahydrofuran, dioxane, monoglyme and diglyme, and aromatichydrocarbons, such as benzene, toluene and xylene, or mixtures of suchsolvents as solvents. To the reaction system of the reaction may beadded amine(s) such as trimethylamine, triethylamine andN-ethyldiisopropyl amine or molecular sieves such as molecular sieves ofthe type 3A (MS-3A) and molecular sieves of the type 4A (MS-4A).

When a catalytic hydrogenation reducing agent is used as a reducingagent, the reaction is usually carried out at about −30 to about 100°C., and preferably about 0 to about 60° C., in a hydrogen atmosphere ofabout atmospheric pressure to about 20 atm, and preferably aboutatmospheric pressure to about 10 atm, or in the presence of a hydrogendonor such as formic acid, ammonium formate, cyclohexene and hydrazinehydrate. The reaction usually finishes in about 1 to about 12 hours. Thecatalytic hydrogenation reducing agent is usually used in an amount ofabout 0.1 to about 40 wt %, and preferably about 1 to about 20 wt %, ofcompound (3).

wherein R¹⁰¹, R¹⁰² and R¹¹² are the same as above; R¹¹³ represents alower alkylsulfonyloxy group, a phenylsulfonyloxy group optionallysubstituted on the phenyl ring with one or more lower alkyl groups, or ahalogen atom.

The lower alkylsulfonyloxy group is a group consisting of a C₁₋₆ alkylgroup and a sulfonyloxy group, examples of which includemethanesulfonyloxy, ethanesulfonyloxy, propanesulfonyloxy,butanesulfonyloxy, pentanesulfonyloxy and hexanesulfonyloxy.

Examples of phenylsulfonyloxy groups optionally substituted on thephenyl ring with one or more lower alkyl groups are benzene sulfonyloxygroups which may be substituted with one to three straight or branchedC₁₋₆ alkyl groups, such as benzenesulfonyloxy, o-toluenesulfonyloxy,m-toluenesulfonyloxy, p-toluenesulfonyloxy, 2-ethylbenzenesulfonyloxy,3-ethylbenzenesulfonyloxy, 4-ethylbenzenesulfonyloxy,2-propylbenzenesulfonyloxy, 3-propylbenzenesulfonyloxy,4-propylbenzenesulfonyloxy, 2,3-dimethylbenzenesulfonyloxy,2,4-dimethylbenzenesulfonyloxy and 2,4,6-trimethylbenzenesulfonyloxy.

Examples of halogen atoms include fluorine, bromine, chlorine and iodineatoms.

The reaction of compound (4) with compound (5) is carried out in asuitable solvent in the presence of a basic compound.

Examples of useful inert solvents include water; aromatic hydrocarbonssuch as benzene, toluene and xylene; ethers such as diethyl ether,tetrahydrofuran, dioxane, 2-methoxyethanol, monoglyme and diglyme;halogenated hydrocarbons such as dichloromethane, dichloroethane,chloroform and carbon tetrachloride; lower alcohols such as methanol,ethanol, isopropanol, butanol, tert-butanol and ethylene glycol;aliphatic acids such as acetic acid; esters such as ethyl acetate andmethyl acetate; ketones such as acetone and methyl ethyl ketone;acetonitrile, pyridine, N-methylpyrrolidone, dimethylsulfoxide,N,N-dimethylformamide and hexamethyl phosphoramide; and mixtures of suchsolvents.

Examples of basic compounds include carbonates such as sodium carbonate,potassium carbonate, sodium hydrogencarbonate, potassiumhydrogencarbonate and cesium carbonate; alkali metal hydroxides such assodium hydroxide, potassium hydroxide and calcium hydroxide; phosphatessuch as potassium phosphate and sodium phosphate; alkali metal hydridessuch as sodium hydride and potassium hydride; alkali metals such aspotassium and sodium; sodium amide; metal alcoholates such as sodiummethylate, sodium ethylate and sodium n-butoxide, sodium tert-butoxideand potassium tert-butoxide; organic bases such as pyridine, imidazole,N-ethyldiisopropylamine, dimethylaminopyridine, triethylamine,trimethylamine, dimethylaniline, N-methylmorpholine,1,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,8-diazabicyclo[5.4.0]undecene-7(DBU) and 1,4-diazabicyclo[2.2.2]octane (DABCO); and mixtures of suchbasic compounds.

Compound (5) is usually used in an amount of at least about 0.1 mole permole of compound (4), and preferably about 0.1 to about 10 moles permole of compound (4).

A basic compound is usually used in an amount of at least about 1 moleper mole of compound (4), and preferably about 1 to about 10 moles permole of compound (4).

For the reaction, compound (4) may be used in a large excess instead ofadding a basic compound.

Alkali metal halogen compound(s), such as sodium iodide and potassiumiodide, may be added to the reaction system of the reaction.

The reaction is usually carried out at about 0 to about 200° C., andpreferably about 0 to about 150° C., and usually completes in about 5minutes to about 80 hours.

wherein R¹⁰¹, R¹⁰² and R¹¹² are the same as above, and X represents ahalogen atom.

The reaction between compounds (6) and (7) and the reaction betweencompounds (8) and (9) are carried out under the same conditions as inthe reaction between compounds (5) and (4) shown by Reaction Scheme 3.

When R¹⁰¹ or R¹⁰² of compound (6) represents any of the groups shown by(1) to (14), (17) to (32) and (40) to (50), the reaction betweencompound (6) and compound (7) is carried out in a suitable solvent inthe presence of a basic compound and catalyst. Similarly, when R¹⁰¹ orR¹⁰² of compound (8) represents any of the groups shown by (1) to (14),(17) to (32) and (40) to (50), the reaction between compound (8) andcompound (9) is carried out in a suitable solvent in the presence of abasic compound and catalyst.

The solvent and basic compound for use in the reaction may each be thesame as those used for the reaction between compounds (5) and (4) shownby Reaction Scheme 3.

Examples of catalysts include palladium compounds such as palladiumacetate, bis(tributyl tin)/bis(dibenzylideneacetone) palladium, copperiodide/2,2′-bipyridyl, bis(dibenzylideneacetone)palladium, tris(dibenzylideneacetone)dipalladium, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and tetrakis(triphenylphosphine) palladium; binaphthyl compounds such asR-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl(R-BINAP),S-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (S-BINAP), andRAC-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl(RAC-BINAP); xanthenecompounds such as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene;borates such as tri-tert-butylphosphine tetrafluoroborate;2,2-bis(diphenyl imidazolidinylidene); and mixtures thereof.

A basic compound is usually used in an amount of at least about 0.5 moleper mole of compound (6) or (8), and preferably about 0.5 to about 40moles per mole of compound (6) or (8).

A catalyst may be used in a usual catalytic amount for compound (6) or(8).

Compounds (7) and (9) are usually used in amounts of at least about 0.5mole per mole of compounds (6) and (8), respectively, and preferablyabout 0.5 to about 3 moles per mole of compounds (6) and (8).

These reactions advantageously proceed usually at room temperature toabout 200° C., and preferably at room temperature to about 150° C., andusually complete in about 0.5 to about 20 hours.

When R¹⁰¹ or R¹⁰² of compound (6) represents any of the groups shown by(1) to (14), (17) to (32) and (40) to (50), the reaction betweencompound (6) and compound (7) is carried out in a suitable solvent inthe presence of a basic compound, copper iodide and ethylene glycol.Similarly, when R¹⁰¹ or R¹⁰² of compound (8) represents any of thegroups shown by (1) to (14), (17) to (32) and (40) to (50), the reactionbetween compound (8) and compound (9) is carried out in a suitablesolvent in the presence of a basic compound, copper iodide and ethyleneglycol.

The solvent and basic compound for use in the reaction may each be thesame as those used for the reaction between compounds (5) and (4) shownby Reaction Scheme 3.

Copper iodide and ethylene glycol may each be used usually in an amountof about 0.01 to 3 moles, and preferably about 0.05 to about 1 mole, permole of compound (6) or (7).

Compounds (7) and (9) are usually used in amounts of at least about 1mole per mole of compounds (6) and (8), respectively, and preferablyabout 1 to about 2 moles per mole of compounds (6) and (8).

These reactions advantageously proceed usually at room temperature toabout 200° C., and preferably at room temperature to about 150° C., andusually completes in about 0.5 to about 50 hours.

When R¹⁰¹ or R¹⁰² of compound (6) represents any of the groups shown by(1) to (14), (17) to (32) and (40) to (50), the reaction betweencompound (6) and compound (7) is carried out in a suitable solvent inthe presence of a silane compound such as sodiumbis(trimethylsilyl)amide. Similarly, when R¹⁰¹ or R¹⁰² of compound (8)represents any of the groups shown by (1) to (14), (17) to (32) and (40)to (50), the reaction between compound (8) and compound (9) is carriedout in a suitable solvent in the presence of a silane compound such assodium bis(trimethylsilyl)amide.

The solvent for use in the reaction may be the same as that used for thereaction between compounds (5) and (4) shown by Reaction Scheme 3.

A silane compound is usually used in an amount of about 0.1 to about 3moles, and preferably about 0.1 to about 2 moles, per mole of compound(6) or (7).

Compounds (7) and (9) are usually used in amounts of at least about 1mole per mole of compounds (6) and (8), respectively, and preferablyabout 1 to about 2 moles per mole of compounds (6) and (8).

These reactions advantageously proceed usually at about 0 to about 200°C., and preferably at about 0 to about 150° C., and usually finishes inabout 0.5 to about 20 hours.

Depending on the kind of compound (7) used, the reaction of compound (6)and compound (7) produces, instead of compound (8), compound (10) shownbelow:

wherein R¹⁰¹ and R¹⁰² are the same as above.

wherein R¹⁰¹ and X are the same as above, R¹⁰⁸ represents any of thegroups shown by (1-1) to (1-37) as defined in General Formula (1), R¹¹⁰and R¹¹¹ are linked together to form, together with the nitrogen atom towhich they are bound, 5 to 7-membered one nitrogen atom-containingsaturated heterocyclic groups which may have one heteroatom selectedfrom the group consisting of nitrogen, oxygen and sulfur, theheterocyclic group optionally being substituted with one to threesubstituents selected from the group consisting of oxo group; loweralkyl groups; lower alkanoyl groups; phenyl lower alkyl groups; phenylgroups optionally substituted on the phenyl ring with one to threemembers selected from the group consisting of halogen atoms and loweralkoxy groups; and pyridyl groups,and b′ represents an integer from 0 to 3.

Examples of 5- to 7-membered one nitrogen atom-containing saturatedheterocyclic groups which may have one heteroatom selected from thegroup consisting of nitrogen, oxygen and sulfur include pyrrolidinyl,piperazinyl, piperidinyl, morpholino, thiomorpholino, homopiperazinyl,homopiperidinyl, imidazolidinyl, thiazolidinyl, isothiazolidinyl,oxazolidinyl, isoxazolidinyl, isothiazolidinyl and pyrazolidinyl.

Examples of the above-mentioned heterocyclic groups substituted with oneto three members selected from the group consisting of oxo group; loweralkyl groups; lower alkanoyl groups; phenyl lower alkyl groups; phenylgroups optionally substituted on the phenyl ring with one to threemembers selected from the group consisting of halogen atoms and loweralkoxy groups; and pyridyl groups:

include the above-mentioned heterocyclic groups substituted with one tothree members selected from the group consisting of oxo groups; straightor branched C₁₋₆ alkyl groups; straight or branched C₁₋₆ alkanoylgroups; phenyl alkyl groups wherein the alkyl moiety is a straight orbranched C₁₋₆ alkyl group; phenyl groups optionally substituted on thephenyl ring with one to three members selected from the group consistingof halogen atoms and straight or branched C₁₋₆ alkoxy groups; andpyridyl groups;

such as 2-oxo-(1-, 3-, 4-, or 5-)pyrrolidinyl, 2-oxo-(1-, 3-, 4-, 5-, or6-)piperazinyl, 4-methyl-(1-, 2-, or 3-)piperazinyl, 4-acetyl-(1-, 2-,or 3-)piperazinyl, 4-ethyl-(1-, 2-, or 3-)piperazinyl, 2-methyl-(1-, 2-,3-, 4-, or 5-)pyrrolidinyl, 2-methyl-(1-, 2-, 3-, 4-, 5-, or6-)piperidinyl, 2,4-dimethyl-(1-, 2-, 3-, 5-, or 6-)piperidinyl,3-methyl-(1-, 2-, 3-, 4-, or 5-)pyrrolidinyl, 2,3,4-trimethyl-(1-, 2-,3-, 5-, or 6-)piperazinyl, 4-acetyl-3-methyl-(1-, 2-, 3-, 5-, or6-)piperazinyl, 3-methyl-(2-, 3-, 4-, 5-, or 6-)morpholino,2-acetyl-(2-, 3-, 4-, 5-, or 6-)morpholino, 4-(2-phenylethyl)-(l-, 2-,or 3-)piperazinyl, 4-(3,4-dichlorophenyl)-(1-, 2-, 3-, or4-)piperazinyl, 4-(4-methoxyphenyl)-(1-, 2-, or 3-)piperazinyl,4-(2-chlorophenyl)-(1-, 2-, or 3-)piperazinyl, 4-[(2-, 3-, or 4-)pyridyl]-(1-, 2-, or 3-)piperazinyl, 4-phenyl-(1-, 2-, or3-)piperazinyl, 4-benzyl-(1-, 2-, or 3-)piperidinyl,4-(3,4-dichlorophenyl)-(1-, 2-, or 3-)morpholino,2-(4-methoxyphenyl)-(1-, 2-, 3-, 4-, or 5-)pyrrolidinyl,4-(2-chlorophenyl)-(1-, 2-, or 3-)piperidinyl, 4-[(2-, 3-, or 4-)pyridyl]-(1-, 2-, or 3-)piperidinyl, 4-phenyl-(1-, 2-, or 3-)piperidinyl, 4-phenyl-3-methyl-(1-, 2-, 3-, 5-, or 6-) piperazinyl,4-[(2-, 3-, or 4-)pyridyl]-2-acetyl-(1-, 2-, 3-, 5-, or 6-)piperazinyl,etc.

The reaction between compound (11) and compound (12) is carried outunder the same conditions as in the reaction between compounds (6) and(7) shown by Reaction Scheme 4.

wherein R¹⁰¹, R¹⁰⁸, b′ and X are the same as above.

Compound (14) is produced by reacting compound (11) with a metal cyanidecompound in a suitable solvent in the presence of a catalyst.

Examples of metal cyanide compounds include sodium cyanide, potassiumcyanide, zinc cyanide, copper cyanide, etc.

The solvent and catalyst for use in the reaction may each be the same asthose used for the reaction between compounds (6) and (7) shown byReaction Scheme 4. The catalyst may be used in a usual catalytic amountfor compound (ii).

The metal cyanide compound is usually used in an amount of at leastabout 1 mole per mole of compound (1.1), and preferably about 1 to about3 moles per mole of compound (11).

The reaction advantageously proceeds usually at room temperature toabout 200° C., and preferably at room temperature to about 150° C., andusually completes in about 0.5 to about 20 hours.

wherein R¹⁰¹, R¹⁰⁸, b′ and X are the same as above, and R¹¹⁴ representsany of the groups shown by (1-3), (1-12), (1-14), (1-19), (1-23),(1-30), and (1-31) in General Formula (1).

The reaction between compound (11) and compound (15) is carried outunder the same conditions as in the reaction between compounds (6) and(7) shown by Reaction Scheme 4.

wherein R¹⁰¹ and R¹¹² are the same as above; R¹¹⁵ represents a phenylgroup, phenyl lower alkyl group, cycloalkyl group, cycloalkyl loweralkyl group, lower alkylthio lower alkyl group, amino-substituted loweralkyl group optionally substituted on the amino group with one or twolower alkyl groups, phenoxy lower alkyl group, or pyridyl lower alkylgroup; and R¹¹⁶ represents a hydrogen atom or lower alkyl group. R¹¹⁵and R¹¹⁶ may alternatively be linked together to form a cycloalkylgroup, provided that the total number of carbon atoms of the portionCH(R¹¹⁶) (R¹¹⁵) in the side chain —(R¹⁰¹) CH(R¹¹⁶) (R¹¹⁵) of compound(18) does not exceed 6.

The reaction between compound (8) and compound (17) is carried out underthe same conditions as in the reaction between compounds (3) and (4)shown by Reaction Scheme 2, except for using compound (17) usually in anamount of at least 1 mole per mole of compound (8), and preferably 1 to5 moles per mole of compound (8).

wherein R¹⁰¹, and R¹¹² are the same as above; a′ represents an integerfrom 0 to 4; R¹⁰³ represents any of the groups shown by (1-1) to (1-37)as defined in General Formula (1), R¹¹⁷ represents a loweralkoxycarbonyl group; and R¹¹⁸ represents a carboxy group.

Compound (20) is produced by the hydrolysis of compound (19).

The hydrolysis of compound (19) is carried out in a suitable solvent orwithout solvent in the presence of an acid or basic compound.

Examples of useful solvents include water; lower alcohols such asmethanol, ethanol, isopropanol and tert-butanol; ketones such as acetoneand methyl ethyl ketone; ethers such as diethyl ether, dioxane,tetrahydrofuran, monoglyme and diglyme; aliphatic acids such as aceticacid and formic acid; esters such as methyl acetate and ethyl acetate;halogenated hydrocarbons such as chloroform, dichloromethane,dichloroethane and carbon tetrachloride; dimethylsulfoxide, N,N-dimethylformamide, and hexamethylphosphortriamide; and mixtures ofsuch solvents.

Examples of acids include mineral acids such as hydrochloric acid,sulfuric acid and hydrobromic acid; and organic acids such as formicacid, acetic acid and sulfonic acids such as trifluoroacetic acid andp-toluenesulfonic acid. Such acids may be used singly or in combination.

Examples of basic compounds include carbonates such as sodium carbonate,potassium carbonate, sodium hydrogencarbonate and potassiumhydrogencarbonate; alkali metal hydroxides such as sodium hydroxide,potassium hydroxide and lithium hydroxide; alkaline earth metalhydroxides such as calcium hydroxide; and other like basic compounds.Such basic compounds may be used singly or in combination.

The hydrolysis reaction advantageously proceeds usually at about 0 toabout 200° C., preferably about 0 to about 150° C., and usually finishesin about 10 minutes to about 30 hours.

Compound (19) is produced by reacting compound (20) with the compoundshown by General Formula (21):

R¹¹⁹OH (21)

wherein R¹¹⁹ represents a lower alkyl group.

Conditions usually selected for esterification reactions are applicableto the reaction between compounds (20) and (21). For example, thereaction between compounds (20) and (21) can be carried out in thepresence of a mineral acid such as hydrochloric acid and sulfuric acid;or a halogenating agent such as thionyl chloride, phosphorusoxychloride, phosphorus pentachloride and phosphorus trichloride.Compound (21) is used in a large excess relative to compound (20). Thereaction advantageously proceeds usually at about 0 to about 150° C.,and preferably about 50 to about 100° C., and usually completes in about1 to about 10 hours.

wherein R¹⁰¹, R¹⁰³, a′ and R¹¹² are the same as above; R¹²⁰ represents alower alkylthio group; and R¹²¹ represents a lower alkylsulfonyl group.

The reaction for producing compound (23) from compound (22) is carriedout in a suitable solvent in the presence of an oxidizing agent.

Examples of useful solvents include water; aliphatic acids such asformic acid, acetic acid and trifluoroacetic acid; alcohols such asmethanol and ethanol; halogenated hydrocarbons such as chloroform anddichloromethane; and mixtures of such solvents.

Examples of useful oxidizing agents include peracids such as performicacid, peracetic acid, pertrifluoroacetic acid, peroxybenzoic acids,m-chloroperoxybenzoic acid and o-carboxyperoxybenzoic acid; hydrogenperoxide; sodium metaperiodate; dichromates such as dichromic acid,sodium dichromate and potassium dichromate; permanganates such aspermanganic acid, sodium permanganate and potassium permanganate; leadsalts such as lead tetraacetate.

An oxidizing agent is usually used in an amount of at least about 2moles per mole of compound (22), and preferably about 2 to 4 moles permole of compound (22).

The reaction is usually carried out at about −10 to about 150° C.,preferably at about −10 to about 100° C., and usually finishes in about1 to about 10 hours.

wherein R¹⁰¹ and R¹¹² are the same as above; R represents a lower alkylgroup having one or more halogen atoms; R¹²³ represents anamino-substituted lower alkyl group optionally substituted on the aminogroup with one or two lower alkyl groups; and R^(123a) represents anamino group optionally substituted on the amino group with one or twolower alkyl groups.

The reaction between compound (24) and compound (25) is carried outunder the same conditions as in the reaction between compounds (5) and(4) shown by Reaction Scheme 3.

Compounds (7) and (9) used as starting materials can be easily produced,for example, by the process shown in Reaction Scheme below:

wherein X is the same as above, and R¹²⁴ represents a lower alkyl grouphaving one or more halogen atoms.

The reaction between compound (27) and compound (28) is carried outunder the same conditions as in the reaction between compounds (5) and(4) shown by Reaction Scheme 3.

Compound (8) as a starting material can be produced, for example, by theprocess shown by Reaction Scheme 13 below:

wherein R¹⁰³, a′, X and R¹¹² are the same as above.

The reaction for producing compound (31) from compound (30) is carriedout, for example, without solvent or in a suitable solvent in thepresence of a reducing agent.

Examples of useful solvents include water; lower alcohols such asmethanol, ethanol, isopropanol, butanol, tert-butanol and ethyleneglycol; acetonitrile; aliphatic acids such as formic acid andacetic-acid; ethers such as diethyl ether, tetrahydrofuran, dioxane,monoglyme and diglyme; aromatic hydrocarbons such as benzene, tolueneand xylene; halogenated hydrocarbons such as dichloromethane,dichloroethane, chloroform and carbon tetrachloride; and mixtures ofsuch solvents.

Examples of a reducing agent include catalytic hydrogenation reducingagents such as palladium black, palladium carbon, platinum oxide,platinum black and Raney nickel, and the like.

A catalytic hydrogenation reducing agent is usually used in an amount ofabout 0.1 to 40 wt %, and preferably about 0.1 to about 20 wt %, ofcompound (30).

The reaction advantageously proceeds by adding basic compound(s) such assodium hydroxide to the reaction system of the reaction.

The reaction is usually carried out at about −30 to about 100° C., andpreferably at about 0 to about 60° C., in a hydrogen atmosphere ofatmospheric pressure to about 20 atm, and preferably atmosphericpressure to about 10 atm. The reaction usually finishes in about 1 toabout 12 hours.

Compounds (3), (5) and (6) used as starting materials can be easilyproduced by, for example, Reaction Scheme shown below:

wherein R¹¹² and X are the same as above, and R¹²⁵ represents an oxogroup, a group represented by R¹¹³, or an amino group, R¹¹³ being thesame as above.

The reaction between compounds (32) and (33) is carried out under thesame conditions as in the reaction between compounds (5) and (4) shownby Reaction Scheme 3 above.

Compound (4) used as a starting material is easily produced, forexample, by the process shown by Reaction Scheme below:

wherein R¹⁰¹, R¹⁰² and X are the same as the above.

The reaction of compound (35) with compound (9) is carried under thesame conditions as described in connection with the reaction of compound(6) with compound (7) shown in Reaction Scheme 4.

Compounds (2), (8), (13), (14), (16), (18), (19), (20), (23) and (26)each of whose R¹¹² is a hydrogen atom, can be produced by replacing R¹¹²with a hydrogen atom in compounds (3), (5), (6), (8), (11), (19), (20),(22) and (24), which are used as starting materials in each reactionshown by Reaction Schemes 2-11, using the thus-obtained compound as astarting material, and reacting the starting material under the sameconditions as in the reactions shown by Reaction Schemes 2-11.

If an optically active substance is used as a starting material(compounds (5), (6), (8), (11), (19), (20), (22) and (24)) in thereactions shown by Reaction Schemes 3-11, optically active compounds(2), (8), (13), (14), (16), (18), (19), (20), (23) and (26) can beproduced by reacting the compound under the same conditions as in thereaction shown by Reaction Schemes 3-11.

It is also possible to produce compound (1) of the present invention byusing compound (2), (8), (13), (14), (16), (18), (19), (20), (23) or(26) produced in the reactions of Reaction Schemes 2-11 as a startingmaterial in the reaction of Reaction Scheme 1 without isolating it.

Each of the objective compounds obtained according to such an abovereaction scheme can be isolated and purified from the reaction mixtureby, for example, after cooling the reaction mixture, performing anisolation procedure such as filtration, concentration, extraction, etc.,to separate a crude reaction product, and then subjecting the crudereaction product to a standard purification procedure such as columnchromatography, recrystallization, etc.

The compound of General Formula (1) according to the present inventionincludes stereoisomers and optical isomers thereof.

Among the starting compounds and object pyrrolidine compound of thepresent invention, those having a basic group or groups may be suitableto form salts with common pharmaceutically acceptable acids. Examples ofsuch acids include hydrochloric acid, hydrobromic acid, nitric acid,sulfuric acid, phosphoric acid and other inorganic acids; methansulfonicacid, p-toluenesulfonic acid, acetic acid, citric acid, tartaric acid,maleic acid, fumaric acid, malic acid, lactic acid and other organicacids, etc.

Among the starting compounds and object pyrrolidine compound of thepresent invention, those having an acidic group or groups may besuitable to form salts with common pharmaceutically acceptable basiccompounds. Examples of such basic compounds include sodium hydroxide,potassium hydroxide, calcium hydroxide, sodium carbonate, potassiumcarbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, etc.

In addition, compounds in the form in which solvate (for example,hydrate, ethanolate, etc.) was added to the starting compounds andobject compound shown in each of the reaction formulae are included ineach of the general formulae.

Pharmaceutical preparations containing the compound of the presentinvention as an active ingredient are explained below.

Such pharmaceutical preparations are obtained by formulating thecompound of the present invention into standard pharmaceuticalpreparations, using typically employed diluents and/or excipients suchas fillers, extenders, binders, wetting agents, disintegrants,surfactants, lubricants, etc.

The form of such pharmaceutical preparations can be selected fromvarious forms according to the purpose of therapy. Typical examplesinclude tablets, pills, powders, solutions, suspensions, emulsions,granules, capsules, suppositories, injections (solutions, suspensions,etc.) and the like.

To form tablets, any of various known carriers can be used, including,for example, lactose, white sugar, sodium chloride, glucose, urea,starch, calcium carbonate, kaolin, crystalline cellulose and otherexcipients; water, ethanol, propanol, simple syrup, glucose solutions,starch solutions, gelatin solutions, carboxymethylcellulose, shellac,methylcellulose, potassium phosphate, polyvinylpyrrolidone and otherbinders; dry starch, sodium alginate, agar powder, laminaran powder,sodium hydrogencarbonate, calcium carbonate, fatty acid esters ofpolyoxyethylenesorbitan, sodium laurylsulfate, stearic acidmonoglycerides, starch, lactose and other disintegrants; white sugar,stearin, cacao butter, hydrogenated oils and other disintegrationinhibitors; quaternary ammonium bases, sodium lauryl sulfate and otherabsorption promoters; glycerol, starch and other wetting agents; starch,lactose, kaolin, bentonite, colloidal silicic acid and other adsorbents;purified talc, stearates, boric acid powder, polyethylene glycol andother lubricants; etc.

Such tablets may be coated with typical coating materials as required,to prepare, for example, sugar-coated tablets, gelatin-coated tablets,enteric-coated tablets, film-coated tablets, double- or multi-layeredtablets, etc.

To form pills, any of various known carriers can be used, including, forexample, glucose, lactose, starch, cacao butter, hydrogenated vegetableoils, kaolin, talc and other excipients; gum arabic powder, tragacanthpowder, gelatin, ethanol and other binders; laminaran, agar and otherdisintegrants; etc.

To form suppositories, any of various known carriers can be used,including, for example, polyethylene glycol, cacao butter, higheralcohols, esters of higher alcohols, gelatin, semisynthetic glycerides,etc.

To form an injection, a solution, emulsion or suspension is sterilizedand preferably made isotonic to blood. Any of various known widely useddiluents can be employed to prepare the solution, emulsion orsuspension. Examples of such diluents include water, ethanol, propyleneglycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol,fatty acid esters of polyoxyethylene sorbitan, etc. In this case, thepharmaceutical preparation may contain sodium chloride, glucose orglycerol in an amount sufficient to prepare an isotonic solution, andmay contain typical solubilizers, buffers, analgesic agents, etc., andfurther, if necessary, coloring agents, preservatives, flavors,sweetening agents, etc., and/or other medicines.

The proportion of the compound of the present invention in thepharmaceutical preparation is not limited and can be suitably selectedfrom a wide range. It is usually preferable that the pharmaceuticalpreparation contain the compound of the present invention in aproportion of 1 to 70 wt. %.

The route of administration of the pharmaceutical preparation of thepresent invention is not limited, and the preparation is administered bya route suitable to the form of the preparation, patient's age and sex,status of the disease, and other conditions. For example, tablets,pills, solutions, suspensions, emulsions, granules and capsules areadministered orally. Injections are intravenously administered singly oras mixed with typical injection transfusions such as glucose solutions,amino acid solutions or the like, or singly administeredintramuscularly, intracutaneously, subcutaneously or intraperitoneally,as required. Suppositories are administered intrarectally.

The dosage of the pharmaceutical preparation is suitably selectedaccording to the method of use, patient's age and sex, severity of thedisease, and other conditions, and is usually about 0.001 to about 100mg/kg body weight/day, and preferably 0.001 to 50 mg/kg body weight/day,in single or divided doses.

Since the dosage varies depending on various conditions, a dosagesmaller than the above range may be sufficient or a dosage larger thanthe above range may be required.

Effect of the Invention

The pyrrolidine compound of the present invention has an effect ofinhibiting reuptake of one, two, or three kinds of monoamines (i.e.,serotonin, norepinephrine, dopamine).

The pyrrolidine compound of the present invention exhibits significantlystronger uptake inhibitory activity to one of these three monoaminesthan known compounds having uptake inhibitory activity to monoamines invitro or ex vivo experiments. In the microdialysis study, thepyrrolidine compound of the present invention also exhibitssignificantly stronger effects for increasing one of these threemonoamines in the rat brain than known compounds having uptakeinhibitory activity to monoamines.

The pyrrolidine compound of the present invention has wider spectrum forthe medical treatment than known antidepressants.

The pyrrolidine compound of the present invention exhibits sufficienttherapeutic effects even after short-term administration.

The pyrrolidine compound of the present invention has excellentbioavailability, little metabolic enzyme inhibitive activity in theliver, little side effects, and is very safe.

The pyrrolidine compound of the present invention exhibits strongactivity in a mouse forced-swimming test/tail suspension test, which isused for screening for antidepressants. The pyrrolidine compound of thepresent invention also exhibits strong activity in the ratforced-swimming test, which is used for screening for antidepressants.The pyrrolidine compound of the present invention also exhibits strongactivity in the reserpine-induced hypothermia model, which is used forscreening for antidepressants

The pyrrolidine compound of the present invention also exhibits strongactivity in the mouse marble-burying behavior test, and a conditionedfear stress model, which are a anxiety- or stress-related diseasemodels.

The pyrrolidine compound of the present invention has an effect ofinhibiting reuptake of one, two, or three kinds of monoamines (i.e.,serotonin, norepinephrine, dopamine), and therefore is effective fortreating various disorders caused by reduced neurotransmission ofserotonin, norepinephrine or dopamine.

Examples of such diseases include hypertension, depressions (e.g., majordepression, bipolar 1 disorder, bipolar 2 disorder, mixed episode,dysthymic disorders, rapid cycler, atypical depression, seasonalaffective disorders, postpartum depression, minor depression, recurrentbrief depressive disorder, intractable depression/chronic depression,double depression, alcohol-induced mood disorders, mixed anxiety &depressive disorders; depressions induced by various physical disorderssuch as Cushing's disease, hypothyroidism, hyperparathyroidism syndrome,Addison's disease, amenorrhea and lactation syndrome, Parkinson'sdisease, Alzheimer's disease, intracerebral bleeding, diabetes, chronicfatigue syndrome and cancers; depression of the middle-aged, seniledepression, depression of children and adolescents, depression inducedby medicines such as interferons), depression induced by adjustmentdisorder, anxiety induced by adjustment disorder, anxiety induced byvarious physical disorders (e.g neuropathy (head trauma, braininfection, inner ear injury), cardiovascular disturbance (cardiacarrest, abnormal cardiac rhythm), endocrine disorder (adrenalhyperfunctio, cachexia exophthalmica), breathing problem (asthma,chronic obstructive pulmonary disease)), generalized anxiety disorders,fears (e.g., agoraphobia, social phobia, and simple phobias),posttraumatic stress syndrome, acute stress syndrome, avoidantpersonality disorders, body dysmorphic disorder, precocious ejaculation,eating disorders (e.g., anorexia nervosa and bulimia nervosa), obesity,chemical dependencies (e.g., to alcohol, cocaine, heroin, phenobarbital,nicotine, and benzodiazepines), cluster headache, migraine, paindisorder, Alzheimer's disease, obsessive-compulsive disorders, panicdisorders, memory disorders (e.g., dementia, amnestic disorder, andage-related cognitive decline (ARCD)), Parkinson's disease (e.g.,dementia caused by Parkinson's disease, neuroleptic agent inducedParkinson's syndrome, tardive dyskinesia), endocrine disorders (e.g.,hyperprolactinaemia), vascular spasm (in particular, in the bloodcirculatory system in the cerebrum), cerebellar ataxia, gastrointestinaltract disorders (including change in movement and secretion), negativesyndrome of schizophrenia, premenstrual syndrome, fibromyalgia syndrome,stress incontinence, Tourette's syndrome, trichotillomania, kleptomania,male impotence, attention deficit hyperactivity disorder (ADHD), chronicparoxysmal hemicrania, chronic fatigue, cataplexy, sleep apnea syndromeand headache (related to angiopathy).

BEST NODE FOR CARRYING OUT THE INVENTION

Preparation Example, Reference Examples, Examples, and PharmacologicalTest Examples are explained below.

Preparation Example 1

The compound of the present invention (100 g), 40 g of Avicel (tradename, manufactured by Asahi Kasei Corporation), 30 g of cornstarch, and2 g of magnesium stearate were mixed, ground, and then subjected totableting using a punch of 10.0 mm in diameter for sugar-coatingtablets. The thus-obtained tablets were coated using a film-coatingagent comprising 10 g of TC-5 (trade name, Shin-Etsu Chemical Co., Ltd.,hydroxypropyl methylcellulose), 3 g of polyethylene glucol 6000, 40 g ofcastor oil, and a suitable amount of ethanol, producing film-coatedtables having the above-mentioned ingredients.

Reference Example 1 Synthesis of3-[(3,4-dichlorophenyl)-(4-fluorophenyl)amino]pyrrolidine-1-carboxylicacid tert-butyl ester

Sodium hydride (0.19 g, 60% in oil) was added to 10 ml of dimethylsulfoxide (DMSO) and stirred at 60° C. for one hour. Subsequently, 1.0 gof (3,4-dichlorophenyl)-(4-fluorophenyl)amine was added to the mixtureand stirred at 60° C. for one hour. A DMSO solution containing 2.0 g of3-(toluene-4-sulfonyloxy) pyrrolidine-1-carboxylic acid tert-butyl esterwas gradually added to the mixture and stirred at 60° C. for 15 hours.Ethyl acetate was added to the reaction solution. The solution was thenwashed with water, and dried over magnesium sulfate. The solvent wasdistilled off under reduced pressure, and the residue was purified bysilica gel column chromatography (n-hexane:ethyl acetate=20:1). Theeluent solvent was distilled off under reduced pressure to therebyobtain 0.29 g of oily brown3-[(3,4-dichlorophenyl)-(4-fluorophenyl)amino]pyrrolidine-1-carboxylicacid tert-butyl ester.

¹H-NMR (CDCl₃) δ ppm:

1.43 (9H, s), 1.74-1.92 (1H, m), 2.04-2.22 (1H, m), 3.10-3.35 (3H, m),3.61-3.85 (1H, m), 4.31-4.48 (1H, m), 6.42 (1H, dd-2.9 Hz, J=8.9 Hz),6.67 (1H, d, J=2.8 Hz), 6.90-7.22 (5H, m).

Reference Example 2 Synthesis of3(S)-[(3,4-dichlorophenyl)phenylamino]pyrrolidine-1-carboxylic acidtert-butyl ester

Sodium hydride (0.36 g, 60% in oil) was added to 20 ml of dimethylsulfoxide (DMSO) and stirred at 60° C. for one hour. Subsequently, 2.0 gof 3,4-dichlorophenyl-phenylamine was added to the mixture and stirredat 60° C. for one hour. A DMSO solution containing 1.5 g of 3(R)-methanesulfonyloxypyrrolidine-1-carboxylic acid tert-butyl ester wasgradually added to the mixture and stirred at 60° C. for 15 hours. Ethylacetate was added to the reaction solution, and the reaction solutionwas then washed with water and dried over magnesium sulfate. The solventwas distilled off under reduced pressure, and the residue was purifiedby silica gel column chromatography (n-hexane:ethyl acetate=20:1). Theeluent solvent was distilled off under reduced pressure to therebyobtain 0.13 g of light brown amorphous solid3(S)-[(3,4-dichlorophenyl)phenylamino]pyrrolidine 1-carboxylic acidtert-butyl ester.

¹H-NMR (CDCl₃) δ ppm:

1.42 (9H, s), 1.73-1.93 (1H, m), 2.05-2.23 (1H, m), 3.10-3.36 (3H, m),3.61-3.83 (1H, m), 4.33-4.50 (1H, m), 6.48 (1H, dd, J=2.9 Hz, J=10.3Hz), 6.74 (1H, d, J=2.8 Hz), 6.96-7.07 (2H, m), 7.16-7.34 (2H, m),7.35-7.46 (2H, m).

Reference Example 3 Synthesis of((S)-1-benzylpyrrolidin-3-yl)-(3-fluorophenyl)amine

A toluene solution containing 2.2 g of (S)-1-benzylpyrrolidin-3-ylamine(12.5 mmol), 2.2 g of 3-bromofluorobenzene (12.5 mmol), 0.31 g of2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP, 0.51 mol), 0.14 g ofbis(dibenzylideneacetone)palladium (Pd(dba)₂, 0.22 mmol), and 1.3 g ofsodium tert-butoxide (13.2 mmol) was heated under reflux under anitrogen atmosphere for 3 hours. The reaction solution was filtered toremove insoluble matter, and ethyl acetate and water were added to thefiltrate to separate the solution into layers. The organic layer waswashed with water, the solvent was distilled off under reduced pressure,and the residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=20:1→1:1). The eluent solvent was distilled offunder reduced pressure to thereby obtain 3.0 g of oily colorless((S)-1-benzylpyrrolidin-3-yl)-(3-fluorophenyl)amine.

¹H-NMR (CDCl₃) δ ppm:

1.59-1.78 (2H, m), 2.21-2.38 (1H, m), 2.39-2.50 (1H, m), 2.55 (1H, dd,J=3.3 Hz, J=9.7 Hz), 2.71-2.85 (2H, m), 3.63 (2H, s), 3.90-4.10 (1H, m),6.24 (1H, dt, J=2.3 Hz, J=11.6 Hz), 6.29-6.41 (2H, m), 7.02-7.11 (1H,m), 7.21-7.39 (5H, m).

Reference Example 4 Synthesis of((S)-1-benzylpyrrolidin-3-yl)-phenylamine((S)-1-benzylpyrrolidin-3-yl)-phenylamine was synthesized using(S)-1-benzylpyrrolidin-3-ylamine and bromobenzene in the same manner asin Reference Example 3 Oily Brown Substance

¹H-NMR (CDCl₃) δ ppm:

1.56-1.78 (2H, m), 2.22-2.39 (1H, m), 2.41-2.58 (1H, m), 2.70-2.84 (2H,m), 3.63 (2H, s), 4.01 (1H, s), 6.57 (2H, d, J=8.5 Hz), 6.64-6.73 (1H,m), 7.11-7.19 (2H, m), 7.21-7.36 (5H, m).

Reference Example 5 Synthesis of((S)-1-benzylpyrrolidin-3-yl)-(3-fluorophenyl)-(4-trifluoromethylphenyl)amine

A toluene solution containing 0.7 g of((S)-1-benzylpyrrolidin-3-yl)-(3-fluorophenyl)amine (2.6 mmol), 0.59 gof 4-bromobenzotrifluoride (2.6 mmol), 65 mg of BINAP (0.1 mmol), 23 mgof palladium acetate (0.1 mmol) and 0.28 g of sodium tert-butoxide (2.9mmol) was heated under reflux under a nitrogen atmosphere for 3 hours.The reaction solution was filtered to remove insoluble matter, and ethylacetate and water were added to the filtrate to separate the solutioninto layers. The organic layer was washed with water and dried overmagnesium sulfate. The solvent was distilled off under reduced pressure,and the residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=20:1→10:1). The eluent solvent was distilled offunder reduced pressure to thereby obtain 0.48 g of oily colorless((S)-1-benzylpyrrolidin-3-yl)-(3-fluorophenyl)-(4-trifluoromethylphenyl)amine.

¹H-NMR (CDCl₃) δ ppm:

1.82-2.01 (1H, m), 2.17-2.31 (1H, m), 2.61-2.78 (3H, m), 3.45 (1H, d,J=12.9 Hz), 3.64 (1H, d, J=12.9 Hz), 4.55 (1H, m), 6.78-6.86 (3H, m),6.88-6.96 (2H, m), 7.19-7.36 (6H, m).

Reference Example 6 Synthesis of 3(S)-(3-chloro-4-fluorophenylamino)pyrrolidine-1-carboxylic acid tert-butyl ester

To a 50 ml of toluene solution containing 5.0 g of3(S)-aminopyrrolidine-1-carboxylic acid tert-butyl ester (27 mmol) and5.7 g of 4-bromo-2-chloro-1-fluorobenzene (27 mmol) were added 1.7 g ofBINAP (2.7 mmol), 0.30 g of palladium acetate (1.3 mmol) and 3.5 g ofsodium tert-butoxide (36 mmol). The mixture was heated under refluxunder a nitrogen atmosphere for 8 hours, and then cooled to roomtemperature. Water was added to the reaction solution, and extractionwith ethyl acetate was performed. After drying over sodium sulfate andconcentration under reduced pressure, the residue was purified by silicagel column chromatography (n-hexane:ethyl acetate=4:1). The solvent wasdistilled off under reduced pressure, and the residue was recrystallizedfrom diethyl ether to thereby obtain 4.76 g of white powdery3(S)-(3-chloro-4-fluorophenylamino) pyrrolidine-1-carboxylic acidtert-butyl ester.

¹H-NMR (CDCl₃) δ ppm:

1.47 (9H, s), 1.78-1.96 (1H, m), 2.10-2.28 (1H, m), 2.10-2.28 (1H, m),3.11-3.30 (1H, m), 3.30-3.56 (2H, m), 3.57-3.79 (2H, m), 3.85-4.03 (1H,m), 6.38-6.47 (1H, m), 6.60 (1H, dd, J=6.0 Hz, J=2.9 Hz), 6.90-7.00 (1H,m).

Reference Example 7 Synthesis of 3(S)-(3-chloro-4-fluorophenylamino)pyrrolidine-1-carboxylic acid tert-butyl ester

To a 50 ml of isopropyl alcohol solution containing 15.0 g of3(S)-aminopyrrolidine-1-carboxylic acid tert-butyl ester (80.5 mmol) and24.8 g of 2-chloro-1-fluoro-4-iodobenzene (96.7 mmol) were added 1.54 gof copper (I) iodide (8.1 mmol), 9.0 ml of ethylene glycol (10.1 mol)and 34.2 g of potassium phosphate (161 mmol), and heated under refluxunder a nitrogen atmosphere for 46 hours. The reaction solution wascooled to room temperature and filtered using Celite. The substanceremained in the filter was washed with ethyl acetate and the filtratewas concentrated under reduced pressure together with the washings, andthe residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=4:1). The solvent was distilled off underreduced pressure, and the residue was recrystallized from diethyl etherto thereby obtain 15.9 g of white powdery3(S)-(3-chloro-4-fluorophenylamino) pyrrolidine-1-carboxylic acidtert-butyl ester.

¹H-NMR (CDCl₃) δ ppm:

1.47 (9H, s), 1.78-1.96 (1H, m), 2.10-2.28 (1H, m), 2.10-2.28 (1H, m),3.11-3.30 (1H, m), 3.30-3.56 (2H, m), 3.57-3.79 (2H, m), 3.85-4.03 (1H,m), 6.38-6.47 (1H, m), 6.60 (1H, dd, J=6.0 Hz, J=2.9 Hz), 6.90-7.00 (1H,m).

Reference Example 8 Synthesis of 3(S)-(3-cyanophenylamino)pyrrolidine-1-carboxylic acid tert-butyl ester

To a toluene solution (7 ml) containing 2.82 g of3(S)-aminopyrrolidine-1-carboxylic acid tert-butyl ester (15 mmol) and1.82 g of 3-bromobenzonitrile (10 mmol) were added 68.5 mg of BINAP(0.11 mmol), 22.5 mg of palladium acetate (0.1 mol) and 3.91 g of cesiumcarbonate (12 mmol). The mixture was heated under reflux under anitrogen atmosphere for 8 hours. After cooling to room temperature,water was added to the reaction solution, and extraction withdichloromethane was performed. After drying over sodium sulfate andconcentration under reduced pressure, the residue was then purified bysilica gel column chromatography (n-hexane:ethyl acetate=4:1). Thepurified product was concentrated to dryness under reduced pressure tothereby obtain, 1.56 g of light yellow powdery3(S)-(3-cyanophenylamino)pyrrolidine-1-carboxylic acid tert-butyl ester.

¹H-NMR (CDCl₃) δ ppm:

1.46 (9H, s), 1.8-2.0 (1H, m), 2.1-2.3 (1H, m), 3.1-3.6 (3H, m), 3.6-3.8(1H, m), 3.9-4.1 (2H, m), 6.7-6.9 (2H, m), 6.99 (1H, d, J=7.6 Hz), 7.23(1H, dd, J=7.6 Hz, J=8.4 Hz).

Reference Example 9 Synthesis of 3(S)-(3-chloro-4-methoxyphenylamino)pyrrolidine-1-carboxylic acid tert-butyl ester

To a 5 ml of toluene solution containing 0.20 g of3(S)-aminopyrrolidine-1-carboxylic acid tert-butyl ester (1.1 mmol) and0.238 g of 2-chloro-3-bromoanisole (1.1 mmol) were added 67.0 mg ofBINAP (0.11 mmol), 24 mg of tris(dibenzylideneacetone)dipalladiumn(0.027 mmol) and 144 mg of sodium tert-butoxide (1.5 mol). The mixturewas heated under reflux under a nitrogen atmosphere at 100° C. for onehour. After cooling to room temperature, the reaction solution wasfiltered using Celite. The filtrate was concentrated under reducedpressure, and the residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=10: 1-3:1). The purified productwas concentrated to dryness under reduced pressure to thereby obtain0.28 g of light yellow amorphous solid3(S)-(3-chloro-4-methoxyphenylamino) pyrrolidine-1-carboxylic acidtert-butyl ester.

¹H-NMR (CDCl₃) δ ppm:

1.47 (9H, s), 1.80-1.90 (1H, m), 2.10-2.20 (1H, m), 3.10-3.25 (1H, m),3.38-3.75 (3H, m), 3.83 (3H, s), 3.92-3.96 (1H, m), 6.47 (1H, dd, J=2.8Hz, J=8.8 Hz), 6.67 (1H, d, J=2.8 Hz), 6.81 (1H, d, J=8.8 Hz).

Reference Example 10 Synthesis of3(S)-(4-methoxyphenylamino)pyrrolidine-1-carboxylic acid tert-butylester

To a 10 ml of ethanol solution containing 0.28 g of3(S)-(3-chloro-4-methoxyphenylamino) pyrrolidine-1-carboxylic acidtert-butyl ester were added a 0.2 ml of a 5 N sodium hydroxide solutionand 0.1 g of 10% palladium carbon. Catalytic reduction was conducted atroam temperature and atmospheric pressure (ordinary pressure). Thereaction solution was filtered using Celite and concentrated underreduced pressure. Water was added to the residue, and extraction withdichloromethane was performed. The extract was dried over magnesiumsulfate and concentrated to dryness under reduced pressure to therebyobtain 0.25 g of yellow amorphous solid3(S)-(4-methoxyphenylamino)pyrrolidine-1-carboxylic acid tert-butylester.

¹H-NMR (CDCl₃) δ ppm:

1.46 (9H, s), 1.79-1.88 (1H, m), 2.10-2.22 (1H, m), 3.12-3.25 (1H, m),3.30-3.52 (3H, m), 3.60-3.75 (4H, m), 3.88-4.00 (1H, m), 6.50-6.58 (2H,m), 6.72-6.80 (2H, m).

Reference Example 11 Synthesis of3(S)-[bis-(3-fluorophenyl)amino]pyrrolidine-1-carboxylic acid tert-butylester

To a 10 ml of toluene solution containing 1.0 g of3(S)-aminopyrrolidine-1-carboxylic acid tert-butyl ester (5.3 mmol) and2.3 g of 3-bromo-1-fluorobenzene (13 mmol) were added 32 mg oftri-tert-butylphosphine.tetrafluoroborate (0.11 mol), 24 mg of palladiumacetate (0.11 mmol) and 1.5 g of sodium tert-butoxide (16 mmol). Themixture was heated under reflux under a nitrogen atmosphere for 8 hours.After cooling to room temperature, water was added to the reactionsolution, and extraction with ethyl acetate was conducted. After dryingover sodium sulfate and concentration under reduced pressure, theresidue was then purified by silica gel column chromatography(n-hexane:ethyl acetate=4:1). The purified product was concentrated todryness under reduced pressure to thereby obtain 1.56 g of oily yellow3(S)-[bis-(3-fluorophenyl)amino]pyrrolidine-1-carboxylic acid tert-butylester.

¹H-NMR (CDCl₃) δ ppm:

1.43 (9H, s), 1.78-1.95 (1H, m), 2.02-2.26 (1H, m), 3.12-3.39 (3H, m),3.65-3.83 (1H, m), 4.35-4.51 (1H, m), 6.61 (2H, dt, J=2.1 Hz, J=11.0Hz), 6.61-6.68 (2H, m), 6.77 (2H, t, J=8.0 Hz), 7.18-7.31 (2H, m).

Reference Example 12 Synthesis of3(S)-[(3,4-dichlorophenyl)-thiazole-2-ylamino]pyrrolidine-1-carboxylicacid tert-butyl ester

To a 150 ml of toluene solution containing 20.0 g of3(S)-(3,4-dichlorophenylamino)pyrrolidine-1-carboxylic acid tert-butylester (60.4 mol) and 15.0 g of 2-bromothiazole (91.5 mmol) were added1.86 g of tri-tert-butylphosphine.tetrafluoroborate (6.4 mmol), 2.88 gof tris(dibenzylideneacetone)dipalladium (3.15 mmol) and 11.6 g ofsodium tert-butoxide (120 mmol). The mixture was heated under refluxunder a nitrogen atmosphere for 9 hours. The reaction solution wascooled to room temperature and filtered using Celite. Water was added tothe filtrate, and extraction with ethyl acetate was conducted. Afterdrying over sodium sulfate and concentration under reduced pressure, theresidue was then purified by silica gel column chromatography (n-hexaneethyl acetate=4:1). The purified product was concentrated to drynessunder reduced pressure to thereby obtain 7.94 g of yellow powdery3(S)-[(3,4-dichlorophenyl)-thiazol-2-ylamino]pyrrolidine-1-carboxylicacid tert-butyl ester.

¹H-NMR (CDCl₃) δ ppm:

1.43 (9H, s), 1.83-2.03 (1H, m), 2.11-2.35 (1H, m), 3.18-3.42 (3H, m),3.73-3.87 (1H, m), 4.97-5.09 (1H, m), 6.53 (1H, d, J=3.5 Hz), 7.14 (1H,dd, J=2.5 Hz, J=8.5 Hz), 7.22 (1H, brs), 7.39 (1H, d, J=2.5 Hz), 7.56(1H, brd, J=8.5 Hz).

Reference Example 13 Synthesis of3(S)-[(3-chloro-4-fluorophenyl)pyridin-3-ylamino]pyrrolidine-1-carboxylicacid tert-butyl ester

To a 10 ml of toluene solution containing 1.0 g of3(S)-(3-chloro-4-fluorophenylamino) pyrrolidine-1-carboxylic acidtert-butyl ester (3.2 mol) and 0.75 g of 3-bromopyridine (4.75 mmol)were added 50 mg of 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene(XANTPHOS, 0.09 mmol), 21.4 mg of palladium acetate (0.10 mmol) and 11.6g of sodium tert-butoxide (120 mol). The mixture was heated under refluxunder a nitrogen atmosphere for 9 hours. After cooling to roomtemperature, the reaction solution was filtered using Celite. Water wasadded to the filtrate, and extraction with ethyl acetate was conducted.After drying over sodium sulfate and concentration under reducedpressure, the residue was then purified by silica gel columnchromatography (n-hexane:ethyl acetate=1:1). The purified product wasconcentrated under reduced pressure to thereby obtain 1.14 g of oily“light yellow3(S)-[(3-chloro-4-fluorophenyl)pyridin-3-ylamino]pyrrolidine-1-carboxylicacid tert-butyl ester.

¹H-NMR (CDCl₃) δ ppm:

1.43 (9H, s), 1.79-1.98 (1H, m), 2.08-2.29 (1H, m), 3.12-3.41 (3H, m),3.65-3.85 (1H, m), 4.38-4.51 (1H, m), 6.83-6.91 (1H, m), 7.00-7.23 (4H,m [including 7.04 ppm (dd, J=2.7 Hz, J=6.4 Hz)]), 8.14 (1H, s), 8.22(1H, d, J=4.4 Hz).

Reference Example 14 Synthesis of3(S)-[(3-chloro-4-fluorophenyl)cyclohexyl amino]pyrrolidine-1-carboxylicacid tert-butyl ester

A 3 ml of acetic acid solution containing 0.60 g of3(S)-[(3-chloro-4-fluorophenyl)amino]pyrrolidine-1-carboxylic acidtert-butyl ester (1.9 mmol) and 0.56 g of cyclohexanone (5.7 mmol) wasstirred at room temperature over night. To the mixture was added 1.21 gof sodium triacetoxyborohydride (5.7 mmol), followed by stirring at roomtemperature for 8 hours. Dichloromethane was added to the reactionsolution, the reaction solution was washed with water and an aqueoussaturated sodium hydrogencarbonate solution, and then dried overmagnesium sulfate. The solvent was distilled off under reduced pressure,and the residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=10:1). The solvent was distilled off from thepurified product under reduced pressure to thereby obtain 0.24 g of oilycolorless3-[(S)-(3-chloro-4-fluorophenyl)cyclohexylamino]pyrrolidine-1-carboxylicacid tert-butyl ester.

¹H-NMR (CDCl₃) δ ppm:

0.81-1.32 (6H, m), 1.44 (9H, s), 1.60-2.00 (6H, m), 2.79-2.93 (1H, m),2.98-3.10 (1H, m), 3.16-3.31 (1H, m), 3.35-3.70 (2H, m), 3.35-3.70 (2H,m), 3.85-4.07 (1H, m), 6.85-7.13 (3H, m).

Reference Example 15 Synthesis of3(S)-[(4-carboxyphenyl)-(3-chloro-4-fluorophenyl)amino]pyrrolidine-1-carboxylicacid tert-butyl ester

To an ethanol solution containing 1.7 g of3(S)-[(3-chloro-4-fluorophenyl)-(4-ethoxycarbonylphenyl)amino]pyrrolidine-1-carboxylicacid tert-butyl ester (3.7 mmol) was added 6 ml of a 5 N sodiumhydroxide solution, followed by stirring at room temperature for 15hours. Dichloromethane and acetic acid were added to the reactionsolution to make the reaction solution acidic. After washing with waterthree times and with an aqueous saturated sodium hydrogencarbonatesolution once, the solvent was distilled off under reduced pressure tothereby obtain 1.50 g of white powdery3(S)-[(4-carboxyphenyl)-(3-chloro-4-fluorophenyl)amino]pyrrolidine-1-carboxylicacid tert-butyl ester.

¹H-NMR (DMSO-d₆) δ ppm:

1.33 (9H, s), 1.72-1.88 (1H, m), 2.06-2.26 (1H, m), 2.99-3.23 (3H, m),3.61 (1H, dd, J=6.4 Hz, J=11.3 Hz), 4.53-4.69 (1H, m), 6.57-6.65 (2H,m), 7.19-7.28 (1H, m), 7.46-7.58 (2H, m), 7.68-7.78 (2H, m), 12.3 (1H,brs).

Reference Example 16 Synthesis of3(S)-[(3-chloro-4-fluorophenyl)-(4-methanesulfonylphenyl)amino]pyrrolidine-1-carboxylicacid tert-butyl ester

To a dichloromethane solution containing 0.45 g of3(S)-[(3-chloro-4-fluorophenyl)-(4-methanesulfanillphenyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester (1.0 mol) was added0.54 g of metachloroperoxybenzoic acid (3.1 mol) at 0° C., followed bystirring at 0° C. for 2 hours. The reaction solution was washed withwater and dried over magnesium sulfate, and the solvent was distilledoff under reduced pressure. Subsequently, the residue was purified bysilica gel column chromatography (n-hexane:ethyl acetate=5:1→1:1). Thesolvent was distilled off from the purified product under reducedpressure to thereby obtain 0.42 g of oily light yellow3(S)-[(3-chloro-4-fluorophenyl)-(4-methanesulfonylphenyl)amino]pyrrolidine1-carboxylic acid tert-butyl ester.

¹H-NMR (CDCl₃) δ ppm:

1.43 (9H, s), 1.80-1.91 (1H, m), 2.11-2.29 (1H, m), 3.01 (3H, s),3.16-3.40 (3H, m), 3.70-3.86 (1H, m), 4.49-4.61 (1H, m), 6.62 (2H, d,J=9.0 Hz), 7.03 (1H, ddd, J=2.6 Hz, J=4.1 Hz, J=8.6 Hz), 7.01-7.06 (1H,m), 7.19-7.23 (1H, m), 7.24-7.31 (1H, m), 7.66-7.74 (2H, m).

Reference Example 17 Synthesis of3(S)-[(3-chloro-4-fluorophenyl)-(6-cyanopyridin-2-yl)amino]pyrrolidine-1-carboxylicacid tert-butyl ester

3(S)-[(6-bromopyridin-2-yl)-(3-chloro-4-fluorophenyl)amino]pyrrolidine-1-carboxylicacid tert-butyl ester (500 mg, 1.06 mmol), zinc cyanide (250 mg, 2.12mmol) and tetrakis(triphenylphosphine)palladium (122 mg, 0.106 mol) weresuspended in 8 ml of dimethylformamide (DMF), followed by stirring undera nitrogen atmosphere at 110° C. for 9 hours. After cooling to roomtemperature, ethyl acetate and water were added to the reaction solutionto separate the solution into layers. The organic layer was washed withwater and dried over magnesium sulfate. The solvent was distilled offunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (n-hexane:ethyl acetate=6:1→3:1). The solvent wasdistilled off from the purified product under reduced pressure tothereby obtain 398 mg of oily colorless3(S)-[(3-chloro-4-fluorophenyl)-(6-cyanopyridin-2-yl)amino]pyrrolidine-1-carboxylicacid tert-butyl ester.

¹H-NMR (CDCl₃) δ ppm:

1.44 (9H, s), 1.74-1.84 (1H, m), 2.03-2.24 (1H, m), 3.08-3.32 (3H, m),3.76-3.86 (1H, m), 5.28-5.38 (1H, m), 6.21 (1H, d, J=8.7 Hz), 7.04-7.11(2H, m), 7.23-7.42 (3H, m).

Reference Example 18 Synthesis of3(S)-[(3-chloro-4-fluorophenyl)-[5-(4-fluorophenyl)pyridin-2-yl]amino)pyrrolidine-1-carboxylic acid tert-butyl ester

3(S)-[(5-bromopyridin-2-yl)-(3-chloro-4-fluorophenyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester (300 mg, 0.64mmol), 4-fluorophenylboric acid (98 mg, 0.7 mmol),tetrakis(triphenylphosphine) palladium (23 mg, 0.02 mmol) and a 2 Maqueous sodium carbonate solution (0.83 ml) were added to toluene (3ml), followed by stirring under a nitrogen atmosphere at 100° C. for 10hours. After cooling to room temperature, ethyl acetate and water wereadded to the reaction solution to separate the reaction solution intolayers. The organic layer was washed with saturated saline, followed bydrying over sodium sulfate. The solvent was distilled off under reducedpressure, and the residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=5:1). The solvent was distilledoff from the purified product under reduced pressure to thereby obtain255 mg of white solid3(S)-{(3-chloro-4-fluorophenyl)-[5-(4-fluorophenyl)pyridin-2-yl]amino}pyrrolidine-1-carboxylicacid tert-butyl ester.

¹H-NMR (CDCl₃) δ ppm:

1.44 (9H, s), 1.78-1.89 (1H, m), 2.05-2.23 (1H, m), 3.07-3.31 (3H, m),3.85 (1H, dd, J=7.1, 10.8 Hz), 5.31-5.42 (1H, m), 6.08 (1H, d, J=8.8Hz), 7.06-7.14 (3H, m), 7.20-7.28 (2H, m), 7.41-7.50 (3H, m), 8.37-8.41(1H, m).

Reference Example 19 Synthesis of3(S)-[(3-chloro-4-fluorophenyl)-(4-thiophene-3-ylphenyl)amino]pyrrolidine-1-carboxylicacid tert-butyl ester

Using3(S)-[(4-bromophenyl)-(3-chloro-4-fluorophenyl)amino]pyrrolidine-1-carboxylicacid tert-butyl ester and 3-thiopheneboric acid,3(S)-[(3-chloro-4-fluorophenyl)-(4-thiophene-3-ylphenyl)amino]pyrrolidine-1-carboxylicacid tert-butyl ester was synthesized in the same manner as in ReferenceExample 9.

Oily Colorless Substance

¹H-NMR (CDCl₃) δ ppm:

1.43 (9H, s), 1.83-1.88 (1H, m), 2.05-2.20 (1H, m), 3.18-3.31 (3H, m),3.63-3.84 (1H, m), 4.40-4.51 (1H, m), 6.71-6.80 (1H, m), 6.85-6.88 (2H,m), 6.94 (1H, dd, J=2.8 Hz, J=6.4 Hz), 7.05-7.10 (1H, m), 7.30-7.45 (3H,m), 7.50-7.55 (2H, m).

Reference Example 20 Synthesis of(S)-{(3-chloro-4-fluorophenyl)-[6-(4-methylpiperazin-1-yl)pyridin-2-yl]amino}pyrrolidine-1-carboxylicacid tert-butyl ester

3(S)-[(6-bromopyridin-2-yl)-(3-chloro-4-fluorophenyl)amino]pyrrolidine-1-carboxylicacid tert-butyl ester (200 mg, 0.43 mmol), 1-methylpiperazine (0.61 ml,0.55 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino) xanthene (XANTPHOS,12 mg, 0.02 mol), tris(dibenzylideneacetone)dipalladium (9 mg, 0.01mmol) and sodium t-butoxide (61 mg, 0.63 mmol) were added to toluene (5ml), followed by stirring under a nitrogen atmosphere at 100° C. for 8hours. Insoluble matter was removed by filtration, and the resultantfiltrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (n-hexane:ethylacetate=4:1). The solvent was distilled off from the purified productunder reduced pressure to thereby obtain 102 mg of oily colorless(S)-{(3-chloro-4-fluorophenyl)-[6-(4-methylpiperazin-1-yl)pyridin-2-yl]amino}pyrrolidine-1-carboxylicacid tert-butyl ester.

¹H-NMR (CDCl₃) δ ppm:

1.44 (9H, s), 1.74-1.89 (1H, m), 2.03-2.21 (1H, m), 2.36 (3H, s),2.51-2.55 (4H, m), 3.08-3.31 (3H, m), 3.54 (4H, brs), 3.64-3.90 (1H, m),5.10-5.23 (1H, m), 5.32 (1H, d, J=8.1 Hz), 6.01 (1H, d, J=8.1 Hz),7.03-7.08 (1H, m), 7.19-7.25 (3H, m).

Reference Example 21 Synthesis of3(S)-[(3-chloro-4-fluorophenyl)-(4-piperidin-1-ylphenyl)amino]pyrrolidine-1-carboxylicacid tert-butyl ester

Using3(S)-[(4-bromophenyl)-(3-chloro-4-fluorophenyl)amino]pyrrolidine-1-carboxylicacid tert-butyl ester and piperidine,3(S)-[(3-chloro-4-fluorophenyl)-(4-piperidin-1-ylphenyl)amino]pyrrolidine-1-carboxylicacid tert-butyl ester was synthesized in the same manner as in ReferenceExample 11.

Oily Colorless Substance

¹H-NMR (CDCl₃) δ ppm:

1.43 (9H, s), 1.55-1.62 (2H, m), 1.68-1.73 (4H, m), 1.74-1.90 (1H, m),2.02-2.18 (1H, m), 3.16-3.29 (7H, m), 3.61-3.81 (1H, m), 4.23-4.38 (1H,m), 6.40-6.46 (1H, m), 6.59-6.62 (1H, m), 6.86-6.92 (5H, m).

Reference Example 22 Synthesis of3(S)-[(3-chloro-4-cyanophenyl)-(3-chloro-4-fluorophenyl)amino]pyrrolidine-1-carboxylicacid tert-butyl ester

To an anhydrous toluene solution containing3(S)-[(3-chloro-4-fluorophenyl)amino]pyrrolidine-1-carboxylic acidtert-butyl ester (0.50 g, 1.6 mmol) and 2-chloro-4-fluorobenzonitrile(0.30 g, 1.9 mmol) was added a 1.45 ml tetrahydrofuran solutioncontaining sodium bis(trimethylsilyl)amide (1.1 M) using a syringe. Themixture was heated under reflux under a nitrogen atmosphere for 8 hoursand cooled to room temperature. Water was added to the reactionsolution, and extraction with diethyl ether was conducted. After dryingover sodium sulfate and concentration under reduced pressure, theresidue was purified by silica gel column chromatography (n-hexane:ethylacetate=4:1). The purified product was concentrated to dryness underreduced pressure to thereby obtain 0.56 g of white amorphous solid3(S)-[(3-chloro-4-cyanophenyl)-(3-chloro-4-fluorophenyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester.

¹H-NMR (CDCl₃) δ ppm:

1.43 (9H, s), 1.76-1.93 (1H, m), 2.11-2.27 (1H, m), 3.15-3.39 (3H, m),3.66-3.87 (1H, m), 4.39-4.55 (1H, m), 6.42 (1H, dd, J=2.5 Hz, J=9.0 Hz),6.57 (1H, d, J=2.5 Hz), 6.98-7.04 (1H, m), 7.20 (1H, dd, J=2.5 Hz, J=6.5Hz), 7.23-7.32 (1H, m), 7.40 (1H, d, J=8.5 Hz).

Reference Example 23 Synthesis of 2-(4-chlorobutoxy)pyridine

To a DMF solution (110 ml) containing 2-pyridinol (10 g, 105 mol) and1-bromo-4-chlorobutane (36 ml, 315 mol) was added potassium carbonate(16 g, 116 mmol), followed by stirring at room temperature for 8 hours.Water (300 ml) was added to the reaction solution, and extraction withethyl acetate (300 ml) was then conducted. The organic layer was washedwith water (300 ml) twice and dried over magnesium sulfate. The solventwas distilled off under reduced pressure, and the residue was thenpurified by silica gel column chromatography (n-hexane:ethylacetate=5:1). The purified product was concentrated under reducedpressure to thereby obtain 3.32 g of oily colorless2-(4-chlorobutoxy)pyridine.

Reference Example 24 Synthesis of 3(S)-[4-(pyridin-2-yloxy)butylamino]pyrrolidine-1-carboxylic acidtert-butyl ester

3(S)-aminopyrrolidine-1-carboxylic acid tert-butyl ester (0.93 g, 5.0mol), 2-(4-chlorobutoxy)pyridine (0.93 g, 5.0 mol), potassium carbonate(0.83 g, 6.0 mmol) and sodium iodide (0.83 g, 5.5 mmol) were suspendedin acetonitrile (20 ml) and heated under reflux for 24 hours. Aftercooling to room temperature, water (50 ml) was added to the reactionsolution and extraction with ethyl acetate (50 ml) was conducted. Theorganic layer was washed with water twice and dried over magnesiumsulfate. The solvent was distilled off under reduced pressure, and theresidue was then purified by silica gel column chromatography(n-hexane:ethyl acetate=3:1). The purified product was concentratedunder reduced pressure to thereby obtain 372 mg of oily colorless3(S)-[4-(pyridin-2-yloxy)butylamino]pyrrolidine-1-carboxylic acidtert-butyl ester.

¹H-NMR (CDCl₃) δ ppm:

1.46 (9H, s), 1.5-1.9 (6H, m), 1.95-2.15 (1H, m), 2.68 (2H, t, J=7 Hz),2.95-3.15 (1H, m), 3.25-3.65 (4H, m), 4.30 (2H, t, J=6.5 Hz), 6.71 (1H,d, J=8.5 Hz), 6.85 (1H, dd, J=5.5 Hz, J=6.5 Hz), 7.5-7.65 (1H, m), 8.14(1H, dd, J=2 Hz, J=5 Hz).

Reference Example 25 Synthesis of3(S)-[(3-chloro-4-fluorophenyl)-(3-chloropropyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester

3(S)-[(3-chloro-4-fluorophenyl)amino]pyrrolidine-1-carboxylic acidtert-butyl ester (3 g, 9.5 mmol), 1-bromo-3-chloropropane (4.7 ml, 48mol) and potassium carbonate (1.97 g, 14.3 mmol) were suspended inN-methylpyrrolidone (NMP, 15 ml), followed by stirring at 100° C. for 8hours. After cooling to room temperature, water was added to thereaction solution, and extraction with ethyl acetate was conducted.After drying the organic layer over sodium sulfate, the solvent wasdistilled off under reduced pressure. The residue was purified by silicagel column chromatography (n-hexane:ethyl acetate=3:1), and the purifiedproduct was concentrated under reduced pressure to thereby obtain 1.0 gof oily colorless3(S)-[(3-chloro-4-fluorophenyl)-(3-chloropropyl)amino]pyrrolidine-1-carboxylicacid tert-butyl ester.

¹H-NMR (CDCl₃) δ ppm:

1.46 (9H, s), 1.7-2.1 (4H, m), 3.1-3.35 (4H, m), 3.35-3.7 (4H, m),3.8-4.1 (1H, m), 6.7-6.9 (1H, m), 6.9-7.1 (2H, m).

Reference Example 26 Synthesis of3(S)-[(3-chloro-4-fluorophenyl)-(3-dimethylaminopropyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester

3(S)-[(3-chloro-4-fluorophenyl)-(3-chloropropyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester (0.5 g, 1.24 mmol),50% dimethylamine solution (1 ml) and sodium iodide (0.37 g, 2.5 mmol)were suspended in DMF (3 ml), followed by stirring at 60° C. for 4hours. After cooling to room temperature, water was added to thereaction solution, and extraction with ethyl acetate was conducted. Theorganic layer was dried over sodium sulfate, and the solvent was thendistilled off under reduced pressure. The residue was purified withbasic silica gel column chromatography (ethyl acetate), and the purifiedproduct was then concentrated under reduced pressure to thereby obtain0.36 g of oily colorless3(S)-[(3-chloro-4-fluorophenyl)-(3-dimethylaminopropyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester.

¹H-NMR (CDCl₃) δ ppm:

1.46 (9H, s), 1.5-1.75 (4H, m), 1.75-2.1 (2H, m), 2.19 (6H, s), 3.0-3.3(4H, m), 3.3-3.75 (2H, m), 3.8-4.2 (1H, m), 6.6-6.8 (1H, m), 6.8-7.1(2H, m).

The compounds shown below were produced in the same manners as in theabove Reference Examples.

TABLE 1

Ref. Ex. No. R1 R2 R3 R4 R5 NMR 27 —H —H —H —H —H ¹H-NMR (CDCl₃) δ ppm1.46 (9H, s), 1.85-1.95 (1H, m), 2.15-2.23 (1H, m), 3.18-3.26 (1H, m),3.39-3.51 (2H, m), 3.62-3.75 (2H, m), 4.00-4.05 (1H, m), 6.60 (2H, d, J= 7.8 Hz), 6.69-6.73 (1H, m), 7.15-7.20 (2H, m). 28 —H —H —OCH₃ —H —H¹H-NMR (CDCl₃) δ ppm 1.46 (9H, s), 1.79-1.88 (1H, m), 2.10-2.22 (1H, m),3.12-3.25 (1H, m), 3.30-3.52 (3H, m), 3.60-3.75 (4H, m), 3.88-4.00 (1H,m), 6.50-6.58 (2H, m), 6.72-6.80 (2H, m). 29 —H —H —CH₃ —H —H ¹H-NMR(CDCl₃) δ ppm 1.46 (9H, s), 1.80-1.92 (1H, m), 2.10-2.22 (1H, m), 2.24(3H, s), 3.15- 3.23 (1H, m), 3.35-3.75 (4H, m), 3.95-4.05 (1H, m),6.51-6.55 (2H, m), 6.95-7.05 (2H, m). 30 —H —H —OCH₃ —Cl —H ¹H-NMR(CDCl₃) δ ppm 1.47 (9H, s), 1.80-1.90 (1H, m), 2.10-2.20 (1H, m),3.10-3.25 (1H, m), 3.38-3.75 (3H, m), 3.83 (3H, s), 3.92-3.96 (1H, m),6.47 (1H, dd, J = 2.8, 8.8 Hz), 6.67 (1H, d, J = 2.8 Hz), 6.81 (1H, d, J= 8.8 Hz). 31 —H —H —F —H —H ¹H-NMR (CDCl₃) δ ppm 1.46 (9H, s),1.75-1.82 (1H, m), 2.00-2.24 (1H, m), 3.03-3.79 (5H, m), 3.80-4.05 (1H,m), 6.51-6.57 (2H, m), 6.90 (2H, dd, J = 8.5 Hz, 8.5 Hz). 32 —H —H —H —F—H 1.47 (9H, s), 1.80-1.99 (1H, m), 2.10-2.26 (1H, m), 3.11-3.35 (1H,m), 3.38-3.57 (2H, m), 3.61-3.77 (1H, m), 3.79-3.91 (1H, m), 3.94- 4.08(1H, m), 6.29 (1H, dt, J = 2.3 Hz and 11.4 Hz), 6.33-6.39 (1H, m), 6.40-6.47 (1H, m), 7.04-7.16 (1H, m) 33 —H —H —F —Cl —H ¹H-NMR (CDCl₃) δ ppm1.47 (9H, s), 1.78-1.96 (1H, m), 2.10-2.28 (1H, m), 2.10-2.28 (1H, m),3.11-3.30 (1H, m), 3.30-3.56 (2H, m), 3.57-3.79 (2H, m), 3.85-4.03 (1H,m), 6.38-6.47 (1H, m), 6.60 (1H, dd, J = 6.0 Hz and 2.9 Hz), 6.90-7.00(1H, m) 34 —H —H —F —CH₃ —H ¹H-NMR (CDCl₃) δ ppm 1.46 (9H, s), 1.7-1.9(1H, m), 2.1-2.2 (1H, m), 2.21 (3H, s), 3.1-3.3 (1H, m), 3.3-3.8 (4H,m), 3.8-4.1 (1H, m), 6.3-6.5 (2H, m), 6.83 (1H, dd, J = 8.9 Hz, J = 8.9Hz) 35 —H —H —H —CN —H ¹H-NMR (CDCl₃) δ ppm 1.46 (9H, s), 1.8-2.0 (1H,m), 2.1-2.3 (1H, m), 3.1-3.6 (3H, m), 3.6-3.8 (1H, m), 3.9-4.1 (2H, m),6.7-6.9 (2H, m), 6.99 (1H, d, J = 7.6 Hz), 7.23 (1H, dd, J = 7.6 Hz, J =8.4 Hz) 36 —H —H —F —CF₃ —H ¹H-NMR (CDCl₃) δ ppm 1.47 (9H, s), 1.76-1.96(1H, m), 2.11-2.27 (1H, m), 3.13-3.32 (1H, m), 3.37-3.53 (2H, m),3.61-3.84 (2H, m), 3.92-4.06 91H, m), 6.66-6.76 (2H, m), 7.02 (1H, dd, J= 9.5 Hz, 9.5 Hz). 37 —H —H —Cl —Cl —H ¹H-NMR (CDCl₃) δ ppm 1.47 (9H,s), 1.80-1.92 (1H, brs), 2.11-2.26 (1H, m), 3.15-3.30 (1H, m), 3.40-3.55(2H, m), 3.60-3.75 (1H, m), 3.79-3.89 (1H, m), 3.91-4.04 (1H, m), 6.42(1H, dd, J = 2.7 Hz and 8.7 Hz), 6.66 (1H, d, J = 2.7 Hz), 7.19 (1H, d,J = 8.6 Hz)

TABLE 2

Ref. Ex. No. R1 NMR 38

¹H-NMR (CDCl₃) δ ppm 1.20-1.30 (2H, m), 1.46 (9H, s), 1.50-1.70 (5H, m),1.80-1.92 (2H, m), 2.05-2.12 (1H, m), 2.92-3.05 (1H, m), 3.06-3.15 (1H,m), 3.25-3.65 (4H, m). 39

¹H-NMR (CDCl₃) δ ppm 1.00-1.30 (5H, m), 1.46 (9H, s), 1.47-1.96 (6H, m),2.00-2.10 (1H, m), 2.40-2.50 (1H, m), 2.91-3.02 (1H, m), 3.25-3.35 (1H,m), 3.38-3.65 (3H, m). 40

¹H-NMR (CDCl₃) δ ppm 1.47 (9H, s), 1.8-2.0 (1H, m), 2.1-2.3 (1H, m),3.1-3.3 (1H, m), 3.4-3.6 (2H, m), 3.6-3.8 (2H, m), 3.9-4.1 (1H, m), 6.88(1H, d, J = 8.3 Hz), 7.0-7.2 (1H, m), 6.8-7.1 (2H, m), 7.9-8.0 (1H, m),8.03 (1H, s) 41

¹H-NMR (CDCl₃) δ ppm 1.47 (9H, s), 1.82-2.00 (1H, m), 2.18-2.32 (1H, m),3.14-3.37 (1H, m), 3.39-3.56 (2H, m), 3.73 (1H, dd, J = 6.0 hz, 11.5Hz), 4.37-4.52 (1H, m), 4.59-4.71 (1H, m), 7.84 (1H, d, J = 2.5 Hz),7.90 (1H, d, J = 1.0 Hz), 8.00 (1H, brs). 42

¹H-NMR (CDCl₃) δ ppm 1.46 (9H, s), 1.79-1.95 (1H, m), 1.97-2.24 (3H, m),2.82 (4H, dd, J = 7.5 Hz, 14.5 Hz), 3.13-3.29 (1H, m), 3.36-3.81 (4H,m), 3.95-4.08 (1H, m), 6.42 (1H, dd, J = 2.0 Hz, 8.0 Hz), 6.52 (1H,brs), 7.04 (1H, d, J = 8.0 Hz). 43

¹H-NMR (CDCl₃) δ ppm 1.46 (9H, s), 1.73-2.01 (1H, m), 2.15-2.31 (1H, m),3.12-3.35 (1H, m), 3.38-3.59 (2H, m), 3.65-3.79 (1H, m), 4.27-4.42 (1H,m), 4.48-4.65 (1H, m), 6.35-6.42 (1H, m), 6.56-6.64 (1H, m), 7.38-7.46(1H, m), 8.04-8.15 (2H, m) 44

¹H-NMR (CDCl₃) δ ppm 1.46 (9H, s), 1.55-1.71 (1H, m), 1.74-2.01 (1H, m),2.16-2.29 (1H, m), 3.19-3.36 (1H, m), 3.40-3.59 (1H, m), 3.63-3.85 (2H,m), 4.01-4.19 (1H, m), 6.71 (1H, dd, J = 2.2 Hz and 8.6 Hz), 6.99 (1H,d, J = 2.2 Hz), 7.13-7.21 (1H, m), 7.35-7.43 (1H, m), 7.59-7.68 (1H, m)45

¹H-NMR (CDCl₃) δ ppm 1.46 (9H, s), 1.88-2.01 (1H, m), 2.19-2.29 (1H, m),3.20-3.36 (1H, m), 3.41-3.59 (2H, m), 3.68-3.90 (2H, m), 4.03-4.18 (1H,m), 6.69 (1H, dd, J = 2.1 Hz and 8.6 Hz), 7.03 (1H, d, J = 2.0 Hz), 7.11(1H, d, J = 5.2 Hz), 7.17 (1H, d, J = 5.3 Hz), 7.59 (1H, d, J = 8.4 Hz)

TABLE 3

Ref. Ex. No. R1 R2 R3 R4 R5 NMR 46 —H —H —Cl —H —H ¹H-NMR (CDCl₃) δ ppm1.42 (9H, s), 1.73-1.93 (1H, m), 2.05-2.23 (1H, m), 3.10-3.36 (3H, m),3.61-3.83 (1H, m), 4.33-4.50 (1H, m), 6.48 (1H, dd, J = 2.9 Hz and J =10.3 Hz), 6.74 (1H, d, J = 2.8 Hz), 6.96-7.07 (2H, m), 7.16-7.34 (2H,m), 7.35-7.46 (2H, m). 47 —H —H —SCH₃ —H —H ¹H-NMR (CDCl₃) δ ppm 1.42(9H, s), 1.75-1.92 (1H, m), 2.0-2.20 (1H, m), 2.46 (3H, s), 3.09- 3.33(3H, m), 3.62-3.83 (1H, m), 4.38-4.55 (1H, m), 6.77-6.88 (4H, m),6.97-7.08 (1H, m), 7.18-7.33 (4H, m) 48 —H —H —Cl —H —H ¹H-NMR (CDCl₃) δppm 1.42 (9H, s), 1.78-1.87 (1H, m), 2.05-2.16 (1H, m), 3.13-3.27 (3H,m), 3.68-3.79 (1H, m), 4.39-4.45 (1H, m), 6.68-6.75 (2H, m), 6.90 (2H,d, J = 7.7 Hz), 7.05-7.15 (1H, m), 7.16-7.25 (2H, m), 7.30-7.40 (2H, m).49 —H —H —H —Cl —H ¹H-NMR (CDCl₃) δ ppm 1.36-1.49 (9H, m), 1.80-1.98(1H, m), 2.03-2.29 91H, m), 3.19-3.41 (3H, m), 3.64-3.89 91H, m),4.44-4.59 (1H, m), 6.52 (2H, d, J = 8.2 Hz), 6.74-6.85 (1H, m),7.12-7.33 (4H, m), 7.46-7.52 (1H, m) 50 —H —H —OCF₃ —H —H ¹H-NMR (CDCl₃)δ ppm 1.42 (9H, s), 1.76-1.91 (1H, m), 2.02-2.21 (1H, m), 3.08-3.86 (4H,m), 4.38-4.53 (1H, m), 8.76 (2H, d, J = 9.0 Hz), 6.90-6.96 (2H, m),7.03-7.22 (3H, m), 7.29-7.40 (2H, m) 51 —H —H —CO₂CH₃ —H —H ¹H-NMR(CDCl₃) δ ppm 1.42 (9H, s), 1.73-1.92 (1H, m), 2.08-2.28 (1H, m),3.12-3.34 (3H, m), 3.69-3.84 (4H, m with s at φ3.84), 4.49-4.65 (1H, m),6.50-6.59 (2H, m), 7.08-7.16 (2H, m), 7.31-7.51 (3H, m), 7.82 (2H, d, J= 6.1 Hz) 52 —H —H —H —Cl —H ¹H-NMR (CDCl₃) δ ppm 1.42 (9H, s),1.73-1.89 (1H, m), 2.02-2.21 (1H, m), 3.09-3.33 (3H, m), 3.62-3.85 (1H,m), 4.35-4.45 (1H, m), 6.42 (2H, d, J = 1.6 Hz), 6.74 (1H, s), 7.02-7.11(2H, m), 7.30-7.50 (3H, m) 53 —H —H —NO₂ —H —H ¹H-NMR (CDCl₃) δ ppm 1.42(9H, s), 1.78-1.95 (1H, m), 2.09-2.28 (1H, m), 3.10-3.38 (3H, m),3.71-3.92 (1H, m), 4.52-4.69 (1H, m), 6.48-6.55 (2H, m), 7.08-7.18 (2H,m), 7.39-7.58 (3H, m), 8.04 (2H, d, J = 8.1 Hz) 54 —H —H —CH₃ —H —H¹H-NMR (CDCl₃) δ ppm 1.42 (9H, s), 1.80-1.85 (1H, m), 2.00-2.15 (1H, m),2.34 (3H, s), 3.18- 3.25 (3H, m), 3.65-3.80 (1H, m), 4.40-4.50 (1H, m),6.73 (2H, d, J = 8.1 Hz), 6.85-6.90 (3H, m), 7.10-7.26 (4H, m). 55 —H —H—CHO —H —H ¹H-NMR (CDCl₃) δ ppm 1.42 (9H, s), 1.80-1.88 (1H, m),2.10-2.20 (1H, m), 3.15-3.30 (3H, m), 3.70-3.85 (1H, m), 4.55-4.65 (1H,m), 6.59 (2H, d, J = 8.4 Hz), 7.10-7.15 (2H, m), 7.40-7.60 (3H, m),7.60-7.70 (2H, m), 9.75 (1H, s). 56 —H —H —Br —H —H ¹H-NMR (CDCl₃) δ ppm1.41 (9H, s), 1.80-1.88 (1H, m), 2.05-2.20 (1H, m), 3.15-3.30 (3H, m),3.65-3.75 (1H, m), 4.38-4.46 (1H, m), 6.65 (2H, d, J = 8.9 Hz), 6.94(2H, d, J = 8.5 Hz), 7.10-7.45 (5H, m). 57 —H —H —OCH₃ —Cl —H ¹H-NMR(CDCl₃) δ ppm 1.43 (9H, s), 1.80-1.88 (1H, m), 2.05-2.15 (1H, m),3.15-3.30 (3H, m), 3.65-3.80 (1H, m), 3.90 (3H, s), 4.38-4.44 (1H, m),6.65-6.70 (2H, m), 6.82-6.90 (3H, m), 7.07 (1H, s), 7.15-7.25 (2H, m).

TABLE 4

Ref. Ex. No. R1 R2 R3 R4 R5 NMR 58 —H —H —OCH₃ —H —H ¹H-NMR (CDCl₃) δppm 1.42 (9H, s), 1.80-1.86 (1H, m), 2.00-2.12 (1H, m), 3.15-3.26 (3H,m), 3.65-3.78 (1H, m), 3.82 (3H, s), 4.40-4.50 (1H, m), 6.63 (2H, d, J =7.6 Hz), 6.75-6.80 (1H, m), 6.86-6.95 (2H, m), 7.00 (2H, d, J = 7.6 Hz),7.10-7.20 (2H, m). 59 —H —H —OC₂H₅ —Cl —H ¹H-NMR (CDCl₃) δ ppm 1.43 (9H,s), 1.47 (3H, t, J = 7.0 Hz), 1.75-1.92 (1H, m), 2.01-2.21 (1H, m),3.11-3.36 (3H, m), 3.64-3.83 (1H, m), 4.10 (2H, q, J = 7.0 Hz),4.36-4.51 (1H, m), 6.67-6.74 (2H, m), 6.83-6.93 (3H, m), 7.04-7.08 (2H,m), 7.14-7.27 (2H, m... 60 —H —H —OC₃H₇ —Cl —H ¹H-NMR (CDCl₃) δ ppm 1.08(3H, t, J = 7.4 Hz), 1.43 (9H, s), 1.79-1.95 (1H, m), 1.96-2.20 (1H, m),3.15-3.38 (3H, m), 3.60-3.85 (1H, m), 3.98 (2H, t, J = 6.5 Hz),4.37-4.51 (1H, m), 6.66-6.73 (2H, m), 6.81-6.93 (3H, m), 7.03-7.09 (1H,m), 7.14-7.28 (2H, m) 61 —H —H —F —CH₃ —H ¹H-NMR (CDCl₃) δ ppm 1.43 (9H,s), 1.7-1.9 (1H, m), 2.0-2.22 (1H, m), 2.24 (3H, s), 3.1-3.4 (3H, m),3.6-3.8 (1H, m), 4.4-4.6 (1H, m), 6.69 (2H, d, J = 7.9 Hz), 6.7-7.1 (4H,m), 7.1-7.3 (2H, m) 62 —H —OCH₃ —F —F —H ¹H-NMR (CDCl₃) δ ppm 1,43 (9H,s), 1.7-1.9 (1H, m), 2.0-2.2 (1H, m), 3.1-3.4 (3H, m), 3.6- 3.8 (1H, m),3.76 (3H, s), 4.3-4.5 (1H, m), 6.0-6.3 (2H, m), 6.92 (2H, d, J = 7.5Hz), 7.0-7.2 (1H, m), 7.2-7.4 (2H, m) 63 —H —H —F —H —H ¹H-NMR (CDCl₃) δppm 1.42 (9H, s), 1.75-1.92 (1H, m), 2.00-2.24 (1H, m), 3.10-3.32 (3H,m), 3.61-3.83 (1H, m), 4.41-4.53 (1H, m), 6.72 (2H, d, J = 8.2 Hz),6.85-7.10 (5H, m), 7.16-7.28 (2H, m) 64 —H —H —H —H —H ¹H-NMR (CDCl₃) δppm 1.30-1.50 (total 9H, m with two ss at δ1.41 and 1.44), 1.79-1.96(1H, m), 2.06-2.32 (1H, m), 3.12-3.41 (3H, m), 3.64-3.91 (1H, m),4.41-4.60 (1H, m), 6.52 (2H, d, J = 8.2 Hz), 6.70-6.81 (1H, m), 7.21-7.41 (5H, m), 7.47-7.58 (1H, m) 65 —H —H —H —H —H ¹H-NMR (CDCl₃) δ ppm1.43 (9H, s), 1.78-1.88 (1H, m), 2.07-2.20 (1H, m), 3.15-3.31 (3H, m),3.65-3.74 (1H, m), 4.40-4.51 (21H, m), 6.55 (2H, dd, J = 1.2 Hz and 4.8Hz), 6.67 (1H, t, J = 1.2 Hz), 6.80-6.85 (1H, m), 6.98-7.03 (1H, m),7.07-7.14 (1H, m), 7.21-7.28 (1H, m), 7.34-7.43 (1H, m)

TABLE 5

Ref. Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 NMR 66 —H —H —Cl —Cl —H —H—H —F —H —H ¹H-NMR (CDCl₃) δ ppm 1.43 (9H, s), 1.73-1.91 (1H, m),2.01-2.21 (1H, m), 3.09-3.38 (3H, m), 3.60-3.82 (1H, m), 4.29-4.48 (1H,m), 6.41 (1H, dd, J = 2.9 Hz and J = 8.9 Hz), 6.67 (1H, d, J = 2.8 Hz),6.90-7.22 (5H, m) 67 —H —H —Cl —Cl —H —H —H —H —H —H ¹H-NMR (CDCl₃) δppm 1.42 (9H, s), 1.73-1.92 (1H, m), 2.05-2.28 (1H, m), 3.12-3.35 (3H,m), 3.63-3.86 (1H, m), 4.35-4.51 (1H, m), 6.39 (1H, dd, J = 2.9 Hz and9.0 Hz), 6.66 (1H, d, J = 2.7 Hz), 7.08-7.28 (4H, m), 7.31-7.45 (1H, m)68 —H —H —H —F —H —H —H —Cl —H —H ¹H-NMR (CDCl₃) δ ppm 1.43 (9H, s),1.74-1.91 (1H, m), 2.02-2.21 (1H, m), 3.10-3.35 (3H, m), 3.62-3.82 (1H,m), 4.39-4.51 (1H, m), 6.39 (1H, dt, J = 1.4 Hz and J = 11.7 Hz), 6.47(1H, d, J = 8.3 Hz), 6.55- 6.65 (1H, m), 6.89-6.98 (2H, m), 7.09-7.21(1H, m), 7.29-7.38 (2H, m) 69 —H —H —H —F —H —H —H —F —H —H ¹H-NMR(CDCl₃) δ ppm 1.43 (9H, s), 1.74-1.92 (1H, m), 2.06-2.29 (1H, m),3.08-3.89 (4H, m), 4.35-4.51 (1H, m), 6.27 (1H, dt, J = 2.3 Hz and J =12.3 Hz), 6.35 (1H, d, J = 7.0 Hz), 6.41-6.53 (1H, m), 7.01- 7.21 (5H,m) 70 —H —H —H —F —H —H —H —SCH₃ —H —H ¹H-NMR (CDCl₃) δ ppm 1.43 (9H,s), 1.75-1.91 (1H, m), 2.01-2.21 (1H, m), 2.50 (1H, s), 3.11-3.32 (3H,m), 3.63-3.83 (1H, m), 4.38-4.51 (1H, m), 6.34 (1H, dt, J = 2.3 Hz and J= 12.1 Hz), 6.42 (1H, d, J = 8.4 Hz), 6.48-6.58 (1H, m), 6.92-7.01 (2H,m), 7.05-7.18 (1H, m), 7.22- 7.31 (2H, m) 71 —H —H —F —H —H —H —H —Cl —H—H ¹H-NMR (CDCl₃) δ ppm 1.42 (9H, s), 1.75-1.92 (1H, m), 2.01-2.20 (1H,m), 3.10-3.33 (3H, m), 3.61-3.81 (1H, m), 4.32-4.99 (1H, m), 6.61 (2H,d, J = 8.8 Hz), 6.94-7.19 (6H, m) 72 —H —H —F —H —H —H —H —F —H —H¹H-NMR (CDCl₃) δ ppm 1.42 (9H, s), 1.80-1.88 (1H, m), 2.00-2.15 (1H, m),3.10-3.30 (3H, m), 3.60-3.75 (1H, m), 4.30-4.38 (1H, m), 6.75-6.85 (4H,m), 6.90-7.00 (4H, m). 73 —H —H —H —F —H —H —F —H —H —H ¹H-NMR (CDCl₃) δppm 1.43 (9H, s), 1.78-1.95 (1H, m), 2.02-2.26 (1H, m), 3.12-3.39 (3H,m), 3.65-3.83 (1H, m), 4.35-4.51 (1H, m), 6.61 (2H, dt, J = 2.1 Hz and J= 11.0 Hz), 6.61-6.68 (2H, m), 6.77 (2H, t, J = 8.0 Hz), 7.18-7.31 (2H,m) 74 —H —H —F —Cl —H —H —F —H —H —H ¹H-NMR (CDCl₃) δ ppm 1.43 (9H, s),1.75-1.92 (1H, m), 2.02-2.35 (1H, m), 3.12-3.38 (3H, m), 3.63-3.85 (1H,m), 4.35-4.50 (1H, m), 6.38 (1H, dt, J = 2.3 Hz and 11.7 Hz), 6.90 (1H,ddd, J = 4.2 Hz, J = 4.2 Hz and J = 8.8 Hz), 7.08 (1H, dd, J = 2.6 Hzand J = 6.5 Hz), 7.11- 7.22 (1H, m) 75 —H —H —F —CH₃ —H —H —CH₃ —F —H —H¹H-NMR (CDCl₃) δ ppm 1.43 (9H, s), 1.8-2.0 (1H, m), 2.0-2.2 (1H, m),2.21 (6H, s), 3.1- 3.4 (3H, m), 3.6-3.8 (1H, m), 4.3-4.5 (1H, m),6.6-6.7 (4H, m), 6.8-7.0 (2H, m) 76 —H —H —F —CH₃ —H —H —F —H —H —H¹H-NMR (CDCl₃) δ ppm 1.43 (9H, s), 1.7-1.9 (1H, m), 2.0-2.2 (1H, m),2.27 (3H, s), 3.1-3.4 (3H, m), 3.6-3.8 (1H, m), 4.3-4.5 (1H, m), 6.26(1H, d, J = 12.4 Hz), 6.3-6.5 (2H, m), 6.8-7.2 (4H, m)

TABLE 6

Ref. Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 NMR 77 —H —H —F —Cl —H —H—CH₃ —H —H —H ¹H-NMR (CDCl₃) δ ppm 1.43 (9H, s), 1.7-1.9 (1H, m),2.0-2.2 (1H, m), 2.40 (3H, s), 3.1-3.4 (3H, m), 3.6-3.8 (1H, m), 4.3-4.5(1H, m), 6.6-6.8 (3H, m), 6.85 (1H, d, J = 6.4 Hz), 6.92 (1H, d, J = 7.3Hz), 6.9-7.1 (1H, m), 7.1-7.3 (1H, m) 78 —H —H —H —F —H —H —CH₃ —H —H —H¹H-NMR (CDCl₃) δ ppm 1.43 (9H, s), 1.7-1.9 (1H, m), 2.0-2.2 (1H, m),2.34 (3H, s), 3.1-3.4 (3H, m), 3.6-3.8 (1H, m), 4.3-4.5 (1H, m), 6.33(1H, d, J = 12.2 Hz), 6.42 (1H, d, J = 8.3 Hz), 6.4-6.6 (1H, m), 6.8-6.9(2H, m), 7.0-7.2 (2H, m), 7.2-7.3 (1H, m) 79 —H —H —F —CH₃ —H —H —H —F—H —H ¹H-NMR (CDCl₃) δ ppm 1.43 (9H, s), 1.7-1.9 (1H, m), 2.0-2.2 (1H,m), 2.22 (3H, s), 3.1-3.4 (3H, m), 3.6-3.8 (1H, m), 4.3-4.5 (1H, m),6.6-6.8 (4H, m), 6.8-7.1 (3H, m) 80 —H —H —H —CH₃ —H —H —H —F —H —H¹H-NMR (CDCl₃) δ ppm 1.43 (9H, s), 1.7-1.9 (1H, m), 2.0-2.2 (1H, m),2.27 (3H, s), 3.1-3.4 (3H, m), 3.6-3.8 (1H, m), 4.4-4.6 (1H, m), 6.54(2H, d, J = 6.5 Hz), 6.74 (1H, d, J = 7.1 Hz), 6.8-7.2 (5H, m) 81 —H —H—H —F —H —H —H —CH₃ —H —H ¹H-NMR (CDCl₃) δ ppm 1.42 (9H, s), 1.7-1.9(1H, m), 2.0-2.2 (1H, m), 2.38 (3H, s), 3.1-3.4 (3H, m), 3.6-3.8 (1H,m), 4.3-4.5 (1H, m), 6.28 (1H, d, J = 12.5 Hz), 6.3-6.5 (2H, m), 6.96(2H, d, J = 8.2 Hz), 7.0-7.3 (3H, m) 82 —H —H —CH₃ —Cl —H —H —F —H —H —H¹H-NMR (CDCl₃) δ ppm 1.43 (9H, s), 1.7-1.9 (1H, m), 2.0-2.2 (1H, m),2.37 (3H, s), 3.1-3.4 (3H, m), 3.6-3.8 (1H, m), 4.3-4.5 (1H, m), 6.38(1H, d, J = 11.9 Hz), 6.46 (1H, d, J = 8.3 Hz), 6.57 (1H, dd, J = 8.1Hz, 7.8 Hz), 6.82 (1H, d, J = 8.1 Hz), 7.02 (1H, s), 7.1-7.3 (2H, m) 83—H —H —Cl —CH₃ —H —H —F —H —H —H ¹H-NMR (CDCl₃) δ ppm 1.43 (9H, s),1.7-1.9 (1H, m), 2.0-2.2 (1H, m), 2.35 (3H, s), 3.1-3.4 (3H, m), 3.6-3.8(1H, m), 4.3-4.5 (1H, m), 6.36 (1H, d, J = 11.9 Hz), 6.43 (1H, d, J =8.3 Hz), 6.55 (1H, dd, J = 8.0 Hz, 8.1 Hz), 6.80 (1H, d, J = 8.3 Hz),6.89 (1H, s), 7.1-7.2 (1H, m), 7.3-7.4 (1H, m) 84 —H —H —F —Cl —H —H —Cl—F —H —H ¹H-NMR (CDCl₃) δ ppm 1.75-1.92 (1H, m), 2.03-2.22 (1H, m),3.11-3.39 (3H, m), 3.61-3.79 (1H, m), 4.26-4.42 (1H, m), 6.42-6.75 (2H,m), 6.87-6.91 (2H, m), 7.06 (1H, dd, J = 8.5 Hz, 8.5 Hz). 85 —H —H —H —F—H —H —CN —H —H —H ¹H-NMR (CDCl₃) δ ppm 1.43 (9H, s), 1.8-1.9 (1H, m),2.1-2.3 (1H, m), 3.1-3.4 (3H, m), 3.6-3.8 (1H, m), 4.4-4.5 (1H, m), 6.68(1H, d, J = 10.2 Hz), 6.75 (1H, d, J = 8.0 Hz), 6.9-7.0 (3H, m), 7.1-7.4(3H, m)

TABLE 7

Ref. Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 NMR 86 —H —H —F —Cl —H —H—CN —H —H —H ¹H-NMR (CDCl₃) δ ppm 1.44 (9H, s), 1.7-1.9 (1H, m), 2.0-2.2(1H, m), 3.1-3.4 (3H, m), 3.6-3.8 (1H, m), 4.3-4.5 (1H, m), 6.7-6.9 (2H,m), 6.9-7.0 (1H, m), 7.0-7.4 (4H, m), 87 —H —H —F —Cl —H —H —H —OCH₃ —H—H ¹H-NMR (CDCl₃) δ ppm 1.43 (9H, s), 1.75-1.91 (1H, m), 2.02-2.18 (1H,m), 3.11-3.35 (3H, m), 3.60-3.79 (1H, m), 3.83 (3H, s), 4.29-4.42 (1H,m), 6.44 (1H, dt, J = 3.5 Hz and J = 8.9 Hz), 6.61 (1H, dd, J = 2.8 Hzand J = 6.1 Hz), 6.86- 7.01 (5H, m) 88 —H —H —F —Cl —H —H —H —CH₃ —H —H¹H-NMR (CDCl₃) δ ppm 1.43 (9H, s), 1.75-1.91 (1H, m), 2.02-2.20 (1H, m),2.37 (1H, s), 3.11-3.38 (3H, m), 3.60-3.83 (1H, m), 4.29-4.49 (1H, m),6.56 (1H, dt, J = 3.6 Hz and J = 9.0 Hz), 6.74 (1H, dd, J = 2.9 Hz and J= 6.3 Hz), 6.86 (2H, d, J = 8.3 Hz), 6.91-7.02 (1H, m), 7.11-7.21 (2H,m) 89 —H —H —F —Cl —H —H —H —OC₂H₅ —H —H ¹H-NMR (CDCl₃) δ ppm 1.32-1.50(2H, m), with s at δ1.42 and t at δ1.43, J = 7.0 Hz), 1.74-1.891 (1H,m), 2.10-2.18 (1H, m), 3.10-3.32 (3H, m), 3.58-3.81 (1H, m), 4.06 (2H,q, J = 7.0 Hz), 4.28-4.42 (1H, m), 6.44 (1H, dt, J = 3.2 Hz and J = 9.0Hz), 6.61 (1H, dd, J = 2.9 Hz and J = 6.1 Hz), 6.84-7.01 (5H, m), withat δ6.96, J = 2.5 Hz) 90 —H —H —F —Cl —H —H —H —C₂H₅ —H —H ¹H-NMR(CDCl₃) δ ppm 1.25 (3H, t, J = 7.5 Hz), 1.43 (9H, s), 1.72-1.91 (1H, m),2.00-2.20 (1H, m), 2.64 (2H, q, J = 7.5 Hz), 3.10- 3.46 (3H, m),3.60-3.81 (1H, m), 4.30-4.49 (1H, m), 6.53-6.61 (1H, m), 6.76 (1H, dd, J= 2.9 Hz and J = 6.3 Hz), 6.87 (1H, d, J = 8.2 Hz), 6.91-7.03 (1H, m),7.12-7.22 (2H, m) 91 —H —H —F —Cl —H —H —H —CO₂C₂H₅ —H —H ¹H-NMR (CDCl₃)δ ppm 1.35 (3H, t, J = 7.1 Hz), 1.43 (9H, s), 1.78-1.95 (1H, m),2.09-2.27 (1H, m), 3.11-3.39 (3H, m), 3.69- 3.85 (1H, m), 4.32 (2H, q, J= 7.1 Hz), 4.93-4.61 (1H, m), 6.57 (2H, d, J = 8.9 Hz), 6.96-7.04 (1H,m), 7.14- 7.29 (2H, m), 7.81-7.94 (2H, m) 92 —H —H —F —Cl —H —H —H —CO₂H—H —H 1H-NMR (DMSO-d6) δ ppm 1.33 (9H, s), 1.72-1.88 (1H, m), 2.06-2.26(1H, m), 2.99-3.23 (3H, m), 3.61 (1H, dd, J = 6.4 Hz and J = 11.3 Hz),4.53-4.69 (1H, m), 6.57-6.65 (2H, m), 7.19-7.28 (1H, m), 7.46-7.58 (2H,m), 7.68-7.78 (2H, m), 12.3 (1H, brs) 93 —H —H —CH₃ —H —H —H —H —F —H —H¹H-NMR (CDCl₃) δ ppm 1.42 (9H, s), 1.74-1.92 (1H, m), 2.00-2.20 (1H, m),2.30 (3H, s), 3.13-3.32 (3H, m), 3.62-3.80 (1H, m), 4.33-4.48 (1H, m),6.74 (2H, d, J = 8.5 Hz), 6.80-6.88 (2H, m), 6.90-7.02 (2H, m),7.03-7.13 (2H, m).

TABLE 8

Ref. Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 NMR  94 —H —H —F —Cl —H —H—H —N(CH₃)₂ —H —H ¹H-NMR (CDCl₃) δ ppm 1,43 (9H, s), 1.70-1.87 (1H, m),2.00-2.13 (1H, m), 2.97 (6H, s), 3.10-3.29 (3H, m), 3.59-3.77 (1H, m),4.28-4.38 (1H, m), 6.41 (1H, dt, J = 3.4, 9.1 Hz), 6.57- 6.61 (1H, m),6.68-6.72 (2H, m), 6.84-6.94 (3H, m).  95 —H —H —F —Cl —H —H —H —CN —H—H ¹H-NMR (CDCl₃) δ ppm 1.43 (9H, s), 1.79-1.92 (1H, m), 2.09-2.17 (1H,m), 3.11-3.32 (3H, m), 3.70-3.89 (1H, m), 4.45-4.53 (1H, m), 6.56 (2H,d, J = 9.0 Hz), 7.02 (1H, dd, J = 2.6, 4.2, 8.7 Hz)), 7.18-7.29 (2H, m),7.43 (2H, d, J = 7.9 Hz).  96 —H —H —F —Cl —H —H —H —CF₃ —H —H ¹H-NMR(CDCl₃) δ ppm 1.43 (9H, s), 1.78-1.90 (1H, m), 2.09-2.23 (1H, m),3.12-3.34 (3H, m), 3.65-3.80 (1H, m), 4.40-4.52 (1H, m), 6.64 (2H, d, J= 8.8 Hz), 7.02 (1H, ddd, J = 2.7, 4.1, 8.6 Hz), 7.15-7.25 (2H, m), 7.42(2H, d, J = 7.7 Hz).  97 —H —H —F —Cl —H —H —OCH₃ —H —H —H ¹H-NMR(CDCl₃) δ ppm 1.43 (9H, s), 1.82-1.90 (1H, m), 2.04-2.18 (1H, m),3.15-3.32 (3H, m), 3.65-3.80 (1H, m), 3.76 (3H, s), 4.33-4.43 (1H, m),6.35 (1H, t, J = 2.3 Hz), 6.59 (1H, dd, J = 1.8, 8.2 Hz), 6.74-6.79 (1H,m), 6.95 (1H, dd, J = 2.7, 6.4 Hz), 7.02-7.10 (1H, m), 7.15-7.22 (1H,m).  98 —H —H —F —Cl —H —H —OC₂H₅ —H —H —H ¹H-NMR (CDCl₃) δ ppm 1.38(3H, t, J = 7.0 Hz), 1.43 (9H, s), 1.80-1.90 (1H, m), 2.03-2.18 (1H, m),3.16-3.23 (3H, m), 3.60-3.69 (1H, m), 3.96 (2H, q, J = 7.0 Hz),4.31-4.41 (1H, m), 6.37 (1H, t, J = 2.2 Hz), 6.41 (1H, dd, J = 1.58, 8.0Hz), 6.59 (1H, d, J = 8.1 Hz), 6.75 (1H, ddd, J = 2.9, 3.9, 8.8 Hz),6.93 (1H, dd, J = 2.8, 6.4 Hz), 7.00-7.08 (1H, m), 7.14-7.25 (1H, m). 99 —H —H —F —Cl —H —H —SCH₃ —H —H —H ¹H-NMR (CDCl₃) δ ppm 1.43 (9H, s),1.78-1.92 (1H, m), 2.04-2.20 (1H, m), 2.44 (3H, s), 3.11-3.33 (3H, m),3.60-3.80 (1H, m), 4.31-4.45 (1H, m), 6.57 (1H, ddd, J = 0.8, 2.3, 8.1Hz), 6.70 (1H, t, 1.9 Hz), 6.76 (1H, ddd, J = 2.8, 4.0, 8.9 Hz),6.90-6.96 (2H, m), 7.03-7.11 (1H, m), 7.16- 7.23 (1H, m). 100 —H —H —F—CH₃ —H —H —H —NO₂ —H —H ¹H-NMR (CDCl₃) δ ppm 1.43 (9H, s), 1.80-1.90(1H, m), 2.01-2.20 (1H, m), 2.31 (3H, s), 3.18-3.38 (3H, m), 3.70-3.88(1H, m), 4.50-4.59 (1H, m), 6.50 (2H, d, J = 9.5 Hz), 6.85-6.97 (2H, m),7.07-7.15 (1H, m), 8.03 (2H, d, J = 7.9 Hz). 101 —H —H —F —CH₃ —H —H —H—CN —H —H ¹H-NMR (CDCl₃) δ ppm 1.43 (9H, s), 1.81-1.93 (1H, m),2.08-2.20 (1H, m), 2.35 (3H, s), 3.18-3.30 (3H, m), 3.65-3.78 (1H, m),4.45-4.55 (1H, m), 6.50 (2H, d, J = 9.5 Hz), 6.83-6.99 (2H, m),7.03-7.15 (1H, m), 7.32-7.43 (2H, m).

TABLE 9

Ref. Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 NMR 102 —H —H —F —CH₃ —H —H—CH₃ —H —H —H ¹H-NMR (CDCl₃) δ ppm 1.43 (9H, s), 1.79-1.90 (1H, m),2.00-2.18 (1H, m), 2.24 (3H, s), 2.27 (3H, s), 3.12-3.30 (3H, m), 3.62-3.71 (1H, m), 4.39-4.50 (1H, m), 6.50-6.52 (2H, m), 6.68-6.72 (1H, m),6.77-6.84 (2H, m), 6.93-7.01 (1H, m), 7.06-7.11 (1H, m). 103 —H —H —F—Cl —H —H —H —C₃H₇ —H —H ¹H-NMR (CDCl₃) δ ppm 0.96 (3H, t, J = 7.3 Hz),1.43 (9H, s), 1.61-1.70 (2H, m), 1.76-1.89 (1H, m), 2.10-2.18 (1H, m),2.51-2.65 (2H, m), 3.11-3.35 (3H, m), 3.62-3.82 (1H, m), 4.31- 4.43 (1H,m), 6.55-6.59 (1H, m), 6.76 (1H, dd, J = 2.9 Hz and 6.3 Hz), 6.86 (2H,d, J = 8.2 Hz), 6.97 (1H, q, J = 9.1 Hz), 7.11-7.19 (2H, m) 104 —H —H —F—Cl —H —H —H —C(CH₃)₃ —H —H ¹H-NMR (CDCl₃) δ ppm 1.31 (9H, s), 1.43 (9H,s), 1.78-1.89 (1H, m), 2.02- 2.19 (1H, m), 3.11-3.34 (3H, m), 3.62-3.80(1H, m), 4.32-4.45 (1H, m), 6.59-6.65 (1H, m), 6.79-6.86 (2H, m with ddat δ6.81, J = 2.8 Hz and 6.3 Hz), 6.99 (1H, q, J = 8.9 Hz), 7.29-7.38(2H, m) 105 —H —H —F —Cl —H —H —H —SCH₃ —H —H ¹H-NMR (CDCl₃) δ ppm 1.43(9H, s), 1.79-1.89 (1H, m), 2.03-2.09 91H, m), 2.51 (3H, s), 3.13-3.4(3H, m), 3.63-3.80 (1H, m), 6.65-6.69 (1H, m), 6.80-6.86 (3H, m), 7.02(1H, q, J = 8.8 Hz), 7.21-7.27 (2H, m) 106 —H —H —F —Cl —H —H —H —SO₂CH₃—H —H ¹H-NMR (CDCl₃) δ ppm 1.43 (9H, s), 1.80-1.91 (1H, m), 2.11-2.2991H, m), 3.01 (3H, s), 3.16-3.40 (3H, m), 3.70-3.86 (1H, m), 4.49-4.61(1H, m), 6.62 (2H, d, J = 9.0 Hz), 7.03 (1H, ddd, J = 2.6 Hz, 4.1 Hz and8.6 Hz), 7.01-7.06 (1H, m), 7.19-7.23 (1H, m), 7.24-7.31 (1H, m),7.66-7.74 (2H, m) 107 —H —H —H —SCH₃ —H —H —H —F —H —H ¹H-NMR (CDCl₃) δppm 1.43 (9H, s), 1.78-1.91 (1H, m), 2.02-2.18 (1H, m), 2.40 (3H, s),3.11-3.30 (3H, m), 3.71-3.80 (1H, m), 4.35-4.50 (1H, m), 6.45 (1H, dd, J= 2.0, 8.1 Hz), 6.56 (1H, brs), 6.75 (1H, d, J = 7.9 Hz), 6.97-7.15 (5H,m). 108 —H —H —H —NO₂ —H —H —CH₃ —F —H —H ¹H-NMR (CDCl₃) δ ppm 1.43 (9H,s), 1.78-1.91 (1H, m), 2.08-2.23 (1H, m), 2.29 (3H, s), 3.14-3.33 (3H,m), 3.71-3.82 (1H, m), 4.45-4.55 (1H, m), 6.75-6.84 (1H, m), 6.89-6.99(2H, m), 7.03-7.28 (2H, m), 7.41-7.55 (1H, m), 7.55-7.58 (1H, m). 109 —H—H —F —CH₃ —H —H —OCH₃ —H —H —H ¹H-NMR (CDCl₃) δ ppm 1.43 (9H, s),1.78-1.90 (1H, m), 2.02-2.19 (1H, m), 2.24 (3H, s), 3.13-3.0 (3H, m),3.63-3.82 (1H, m), 3.73 (3H, s), 4.39-4.52 (1H, m), 6.19 (1H, s), 6.25-6.28 (1H, m), 6.38-6.41 (1H, m), 6.80-6.91 (2H, m), 6.92-7.06 (1H, m ),7.07-7.13 (1H, m).

TABLE 10

Ref. Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 NMR 110 —H —H —Cl —Cl —H —H—F —H —H —H ¹H-NMR (CDCl₃) δppm 1.43 (9H, s), 1.78-1.92 (1H, m),2.03-2.23 (1H, m), 3.12-3.36 (3H, m), 3.61-3.82 (1H, m), 4.31-4.50 (1H,m), 6.57 (1H, dt, J = 2.2Hz and 10.7Hz), 6.61-6.66 (1H, m), 6.69 (1H,dd, J = 2.7Hz and 8.7Hz), 6.75-6.85 (1H, m), 6.95 (1H, d, J = 2.7Hz),7.19-7.39 (2H, m) 111 —H —H —F —Cl —H —H —H

—H —H ¹H-NMR (CDCl₃) δppm 1.43 (9H, s), 1.59-1.75 (3H, m), 1.79-1.92(3H, m), 1.95-2.15 (2H, m), 3.11-3.32 (3H, m), 3.58-3.79 (2H, m),3.89-3.99 (1H, m), 4.30-4.43 (1H, m), 5.30 (1H, s), 6.43-6.44 (1H, m),6.62-6.67 (1H, m), 6.85-6.97 (3H, m), 7.02-7.10 (2H, m) 112 —H —H —F—CF₃ —H —H —Cl —F —H —H ¹H-NMR (CDCl₃) δppm 1.43(9H, s), 1.76-1.91(1H,m), 2.03-2.09(1H, m), 3.11- 3.37(3H, m), 3.61-3.79(1H, m), 4.32-4.45(1H,m), 6.73-6.79(1H, m), 6.93-6.98(2H, m), 7.01-7.04(1H, m), 7.05-7.16(2H,m)

TABLE 11

Ref. Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 NMR 113 —H —H —H —H —H —H —H —H—H ¹H-NMR (CDCl₃) δppm 1.42 (9H, s), 1.68-1.72 (1H, m), 1.99-2.21 (1H,m), 3.06-3.31 (3H, m), 3.83 (1H, dd, J = 7.2Hz and 10.7Hz), 5.32-5.49(1H, m), 5.96 (1H, d, J = 6.0Hz), 6.52-6.65 (1H, m), 7.10-7.29 (3H, m),7.31-7.52 (3H, m), 8.15-8.23 (1H, m) 114 —H —F —H —H —H —H —H —H —H¹H-NMR (CDCl₃) δppm 1.43 (9H, s), 1.75-1.94 (1H, m), 2.09-2.38 (1H, m),3.12-3.49 (3H, m), 3.70-3.85 (1H, m), 4.40-4.60 (1H, m), 6,49-6.61 (2H,m), 6.68-6.79 (1H, m), 7.16-7.31 (3H, m), 8.27(1H, s), 8.36-8.44(1H, m)115 —H —Cl —F —H —H —H —H —H —H ¹H-NMR (CDCl₃) δppm 1.45 (9H, s),1.70-1.89 (1H, m), 2.02-2.25 (1H, m), 3.04-3.49 (3H, m), 3.84 (1H, dd, J= 7.1Hz and 10.8Hz), 5.30-5.49 (1H, m), 6.02 (1H, d, J = 8.6Hz),6.58-6.72 (1H, m), 7.02-7.39 (4H, m), 8.16-8.28 (1H, m) 116 —H —H —H —H—H —CH₃ —H —H —H ¹H-NMR (CDCl₃) δppm 1.43 (9H, s), 1.68-1.89 (1H, m),2.00-2.20 (1H, m), 2.43 (3H, d, J = 4.6Hz), 3.09-3.30 (3H, m), 3.72-3.95 (1H, m), 5.39-5.58 (1H, m), 5.74 1H, d, J = 8.5 Hz), 6.33-6.53 (1H,m), 7.05-7.20 (3H, m), 7.29-7.50 31H, m) 117 —H —H —H —H —H —H —CH₃ —H—H ¹H-NMR (CDCl₃) δppm 1.42 (9H, s), 1.68-1.85 (1H, m), 1.95-2.20 (4H, mwith s at δ2.17), 3.03-3.31 (3H, m), 3.75-3.88 (1H, m), 5.24-5.47 (1H,m), 5.92 (1H, d, J = 8.6Hz), 7.07 (1H, d, J = 8.6Hz), 7.11-7.19 (2H, m),7.29-7.31 (3H, m), 8.00 (1H, d, J = 5.2Hz) 118 —H —H —H —H —H —H —H —CH₃—H ¹H-NMR (CDCl₃) δppm 1.42 (9H, s) 1.65-1.87 (1H, m), 1.95-2.12 (1H,m), 2.17 (3H, s), 3.05-3.31 (3H, m), 3.78-3.88 (1H, m), 5.21-5.45 (1H,m), 5.92 (1H, d, J = 8.6Hz), 7.07 (1H, d, J = 8.6Hz), 7.10-7.20 (2H, m),7.28-7.31 (3H, m), 7.96-8.05 (1H, m) 119 —H —Cl —F —H —H —H —CH₃ —H —H¹H-NMR (CDCl₃) δppm 1.43 (9H, s) 1.69-1.71 (1H, m), 1.90-2.10 (1H, m),2.19 (3H, s), 3.01-3.36 (3H, m), 3.76-3.85 (1H, m), 5.19-5.36 (1H, m),5.96 (1H, d, J = 8.6Hz), 7.01- 7.06(1H, m), 7.07-7.17 (2H, m), 7.18-7.26(2H, m), 8.01 (1H, d, J = 12.5Hz) 120 —H —Cl —F —H —H —H —H —CH₃ —H¹H-NMR (CDCl₃) δppm 1.43 (9H, s), 1.68-1.81 (1H, m), 2.02-2.20 (4H, mwith s at δ2.12), 3.04-3.32 (3H, m), 3.78-3.84 (1H, m) 5.29-5.42 (1H,m), 5.80 (1H, s), 6.40-6.53 (1H, m), 7.02-7.10 (1H, m), 7.11-7.25 (2H,m), 8.05 (1H, dd, J = 5.0Hz and 12.2Hz)

TABLE 12

Ref. Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 NMR 121 —H —Cl —F —H —H —CH₃ —H—H —H ¹H-NMR (CDCl₃) δppm 1.44 (9H, s), 1.68-1.82 (1H, m), 2.00-2.19(1H, m), 2.39-2.49 (3H, m), 3.02-3.37 (3H, m), 3.74- 3.84 (1H, m),5.32-5.51 (1H, m), 5.70-5.81 (1H, m), 6.41-6.57 (1H, m), 7.04 (1H, ddd,J = 2.6Hz, 4.3Hz and 8.7Hz), 7.10-7.30 (3H, m) 122 —H —Cl —F —H —H —H—Cl —H —H ¹H-NMR (CDCl₃) δppm 1.43 (9H, s), 1.62-1.82 (1H, m), 2.01-2.22(1H, m), 3.03-3.31 (3H, m), 3.79 (1H, dd, J = 7.0, 10.8Hz), 5.21-5.27(1H, m), 5.96 (1H, d, J = 9.0Hz), 7.04 (1H, ddd, J = 2.6, 4.2, 8.6),7.20- 7.26 (4H, m), 8.12-8.14 (1H, m). 123 —H —CF₃ —F —H —H —H —H —H —H¹H-NMR (CDCl₃) δppm 1.43 (9H, s), 1.63-1.79 (1H, m), 2.02-2.26 (1H, m),3.03-3.35 (3H, m), 3.84 (1H, dd, J = 7.0Hz, 11.0Hz), 5.30-5.41 (1H, m),5.97 (1H, d, J = 8.5Hz), 6.62-6.73 (1H, m), 7.26-7.47 (4H, m), 8.18-8.26(1H, m). 124 —H —CH₃ —F —H —H —H —Cl —H —H ¹H-NMR(CDCl₃) δppm 1.43 (9H,s), 1.68-1.82 (1H, m), 2.00-2.19 (1H, m), 2.29 (3H, s), 3.10-3,29 (3H,m), 3.79 (1H, dd, J = 7.1, 10.8Hz), 5.15-5.32 (1H, m), 5.93 (1H, d, J =9.1Hz), 6.90-6.99 (2H, m), 7.01-7.21 (2H, m), 8.11-8.12 (1H, m). 125 —H—H —F —H —H —H —Cl —H —H ¹H-NMR (CDCl₃) δppm 1.42 (9H, s), 1.73-1.82(1H, m), 2.00-2.17 (1H, m), 3.06-3.29 (3H, m), 3.79 (1H, dd, J = 7.1,10.8Hz), 5.15-5.32 (1H, m), 5.92 (1H, d, J = 9.0Hz), 7.07-7.27 (5H, m),8.12 (1H, d, J = 4.7). 126 —H —Cl —F —H —H —H —H —CF₃ —H ¹H-NMR (CDCl₃)δppm 1.43 (9H, s), 1.7-1.9 (1H, m), 2.0-2.2 (1H, m), 3.0-3.4 (3H, m),3.7-3.9 (1H, m), 5.2-5.4 (1H, m), 6.15 (1H, s), 6.82 (1H, d, J = 5.0Hz), 7.0-7.1 (1H, m), 7.2-7.4 (2H, m), 8.3-8.4 (1H, m) 127 —H —Cl —F —H—H —OCH₃ —H —H —H ¹H-NMR (CDCl₃) δppm 1.43 (9H, s), 1.7-1.9 (1H, m),2.0-2.2 (1H, m), 3.1-3.4 (3H, m), 3.7-3.9 (1H, m), 3.90 (3H, s), 5.1-5.3(1H, m), 5.51 (1H, d, J = 8.1 Hz), 6.09 (1H, d, J = 8.3 Hz), 7.0-7.1(1H, m), 7.2-7.4 (3H, m)

TABLE 13

Ref. Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 NMR 128 —H —Cl —F —H —H —H —H —H—H ¹H-NMR (CDCl₃) δppm 1.43 (9H, s), 1.79-1.98 (1H, m), 2.08-2.29 (1H,m), 3.12-3.41 (3H, m), 3.65-3.85 (1H, m), 4.38-4.51 (1H, m), 6.83-6.91(1H, m), 7.00-7.23 (4H, m with dd at δ7.04, J = 2.7Hz and J = 6.4Hz),8.14(1H, s), 8.22 (1H, d, J = 4.4Hz) 129 —H —CH₃ —F —H —H —H —H —H —H¹H-NMR (CDCl₃) δppm 1.43 (9H, s), 1.7-1.9 (1H, m), 2.0-2.2 (1H, m), 2.26(3H, s), 3.1-3.4 (3H, m), 3.6-3.8 (1H, m), 4.3- 4.5 (1H, m), 6.8-7.1(5H, m), 7.9-8.1 (2H, m) 130 —H —H —H —H —H —H —F —H —H ¹H-NMR (CDCl₃)δppm 1.43 (9H, s), 1.73-1.96 (1H, m), 2.01-2.29 (1H, m), 3.11-3.40 (3H,m), 3.64-3.86 (1H, m), 4.37-4.56 (1H, m), 6.79-6.94 (3H, m), 7.02-7.15(1H, m), 7.19-7.40 (3H, m), 7.80 (1H, brs) 131 —H —Cl —F —H —H —H —OCH₃—H —H ¹H-NMR (CDCl₃) δppm 1.43 (9H, s), 1.7-1.9 (1H, m), 2.0-2.2 (1H,m), 3.1- 3.4 (3H, m), 3.6-3.8 (1H, m), 3.96 (3H, s), 4.3-4.5 (1H, m),6.50 (1H, d, J = 9.0 Hz), 6.67 (1H, d, J = 6.0 Hz), 6.78 (1H, d, J = 8.8Hz), 6.9-7.0 (1H, m), 7.26 (1H, d, J = 8.8 Hz), 7.92 (1H, s) 132 —H —Cl—H —H —H —H —H —H —H ¹H-NMR (CDCl₃) δppm 1.41 (9H, s), 1.7-1.9 (1H, m),2.1-2.3 (1H, m), 3.1- 3.4 (3H, m), 3.7-3.9 (1H, m), 4.4-4.6 (1H, m),6.71 (1H, d, J = 6.9 Hz), 6.83 (1H, s), 7.03 (1H, dd, J = 6.9 Hz, J =7.8 Hz), 7.1-7.3 (2H, m), 8.24 (1H, s), 8.36 (1H, s)

TABLE 14

Ref. Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 NMR 133 —H —F —F —H —H —H —H —H—H ¹H-NMR (CDCl₃) δppm 1.43 (9H, s), 1.8-2.0 (1H, m), 2.1-2.3 (1H, m),3.1-3.4 (3H, m), 3.6-3.8 (1H, m), 4.4-4.6 (1H, m), 6.6-6.7 (1H, m),6.7-6.9 (1H, m), 7.0-7.3 (3H, m), 8.16 (1H, d, J = 6.6 Hz), 8.25 (1H, s)134 —H —F —Cl —H —H —H —H —H —H ¹H-NMR (CDCl₃) δppm 1.42 (9H, s),1.8-1.9 (1H, m), 2.1-2.3 (1H, m), 3.1-3.4 (3H, m), 3.7-3.9 (1H, m),4.4-4.5 (1H, m), 6.47 (1H, d, J = 8.1 Hz), 6,54 (1H, d, J = 11.2 Hz),7.2-7.4 (3H, m), 8.30 (1H, s), 8.45 (1H, s) 135 —H —Cl —Cl —H —H —H —H—H —H ¹H-NMR (CDCl₃) δppm 1.43 (9H, s), 1.8-1.9 (1H, m), 2.1-2.3 (1H,m), 3.1-3.4 (3H, m), 3.7-3.9 (1H, m), 4.4-4.5 (1H, m), 6.63 (1H, d, J =8.7 Hz), 6.90 (1H, s), 7.2- 7.4 (3H, m), 8.27 (1H, s), 8.41 (1H, s) 136—H —CF₃ —F —H —H —H —H —H —H ¹H-NMR (CDCl₃) δppm 1.43 (9H, s), 1,74-1.94(1H, m), 2.06-2.28 (1H, m), 3.12-3.38 (3H, m), 3.65-3.82 (1H, m), 4.38-4.56 (1H, m), 7.01-7.25 (5H, m), 8.16 (1H, s), 8.28 (1H, d, J = 4.5Hz).137 —H —H —F —H —H —H —H —H —H ¹H-NMR (CDCl₃) δppm 1.43 (9H, s),1,79-1.97 (1H, m), 2.03-2.23 (1H, m), 3.11-3.29 (3H, m), 3.63-3.79 (1H,m), 4.38- 4.50 (1H, m), 6.83-6.92 (1H, m), 7.01-7.12 (6H, m), 8.01-8.10(2H, m).

TABLE 15

Ref. Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 NMR 138 —H —H —H —H —H —H —H —H—H ¹H-NMR (CDCl₃) δppm 1.42 (9H, s), 1.77-1.92 (1H, m), 1.95-2.27 (1H,m), 3.10-3.38 (3H, m), 3.68-3.89 (1H, m), 4.41-4.61 (1H, m), 6.32-6.40(2H, m), 7.08-7.15 (2H, m), 7.38-7.54 (3H, m), 8.12-8.22 (1H, m) 139 —H—Cl —F —H —H —H —H —H —H ¹H-NMR (CDCl₃) δppm 1.43 (9H, s), 1.73-1.95(1H, m), 2.07-2.27 (1H, m), 3.12-3.38 (3H, m), 3.65-3.84 (1H, m),4.41-4.61 (1H, m), 6.32-6.41 (2H, m), 6.99-7.08 (1H, m), 7.18-7.32 (2H,m with dd at δ7.21, J = 2.5Hz and J = 6.6Hz), 8.12- 8.31 (2H, m) 140 —H—Cl —F —H —H —H —H —CH₃ —H ¹H-NMR (CDCl₃) δppm 1.43 (9H, s), 1.8-2.0(1H, m), 2.1-2.3 (1H, m), 2.40 (3H, s), 3.1-3.4 (3H, m), 3.7-3.9 (1H,m), 4.4-4.6 (1H, m), 6.1-6.3 (2H, m), 6.9-7.1 (1H, m), 7.1-7.3 (2H, m),8.12 (1H, d, J = 5.0 Hz)

TABLE 16

Ref. Ex. No. R1 R2 R3 R4 R5 R6 NMR 141 —H —H —F —H —H

¹H-NMR (CDCl₃) δppm 0.80-1.36 (6H, m), 1-44 (9H, s), 1.61-1.99 (6H, m),2.93 (1H, m), 2.95-3.09 (1H, m), 3.15-3.31 (1H, m), 3.33- 3.68 (2H, m),3.87-4.07 (1H, m), 6.86-6.98 (2H, m), 6.98- 7.07 (2H, m) 142 —H —H —F —H—H

¹H-NMR (CDCl₃) δppm 1.44(9H, s), 1.81-1.81 (3H, m), 1.89-2.01 (1H, m),2.95- 3.70 (7H, m), 3.88-4.01 (1H, m), 6.88-7.10 (4H, m) 143 —H —H —F—Cl —H

¹H-NMR (CDCl₃) δppm 1.19-1.74 (18H, m with s at δ1.46), 1.89-2.02 (1H,m), 2.97-3.63 5H. m), 3.71-3.91 (1H, m), 6.89-7.07 (2H, m), 7.10 (1H, d,J = 6.4Hz) 144 —H —H —F —H —H

¹H-NMR (CDCl₃) δppm 1.43 (9H, s), 1.8-2.0 (1H, m), 2.0-2.2 (1H, m),3.1-3.4 (3H, m), 3.6-3.8 (1H, m), 4.2-4.4 (1H, m), 5.95 (2H, s), 6.4-6.5(2H, m), 6.6-6.8 (3H, m), 6.8-7.0 (2H, m) 145 —H —H —F —Cl —H

¹H-NMR (CDCl₃) δppm 1.44 (9H, s), 1.7-1.9 (1H, m), 2.0-2.2 (1H, m),3.1-3.4 (3H, m), 3.6-3.8 (1H, m), 4.2-4.4 (1H, m), 6.00 (2H, s), 6.4-6.5(3H, m), 6.66 (1H, d, J = 6.2 Hz), 6.7-7.0 (2H, m) 146 —H —H —H —F —H

¹H-NMR (CDCl₃) δppm 1.43 (9H, s), 1.8-1.9 (1H, m), 2.0-2.2 (1H, m),3.1-3.4 (3H, m), 3.6-3.8 (1H, m), 4.3-4.5 (1H, m), 6.02 (2H, s), 6.27(1H, d, J = 12.6 Hz), 8.37 (1H, d, J = 8.5 Hz), 6.4- 6.5 (1H, m),6.5-6.7 (2H, m), 6.8-8.9 (1H, m), 7.0-7.2 (1H, m) 147 —H —H —F —Cl —H

¹H-NMR (CDCl₃) δppm 1.43 (9H, s), 1.78-1.90 (1H, m), 2.04-2.18 (3H, m),2.79- 2.95 (4H, m), 3.13-3.32 (3H, m), 3.61-3.80 (1H, m), 4.27 4.45 (1H,m), 6.50-6.57 (1H, m), 6.61-6.79 (2H, m), 6.83 (1H, s), 6.88-7.02 (1H,m), 7.13-7.22 (1H, m). 148 —H —H —F —Cl —H

¹H-NMR (CDCl₃) δppm 1.45 (9H, s), 1.7-1.9 (1H, m), 2.0-2.2 (1H, m),3.1-3.4 (3H, m), 3.6-3.8 (1H, m), 4.27 (4H, s), 4.3-4.5 (1H, m), 8.4-6.6(3H, m), 6.68 (1H, d, J = 6.2 Hz), 6.84 (1H, dd, J = 9.1 Hz, J = 9.1Hz), 6.9-7.0 (1H, m) 149 —H —H —H —H —H

¹H-NMR (CDCl₃) δppm: 1.41 (9H, s), 1.8-2.6 (1H, m), 2.05-2.3 (1H, m),3.1- 3.4 (3H, m), 3.7-3.95 (1H, m), 4.5-4.7 (1H, m), 6.85- 7.0 (3H, m),7.08 (1H, dd, J = 7, 7Hz), 7.2-7.5 (5H, m), 7.6-7.8 (3H, m). 150 —H —H—H —H —H

¹H-NMR (CDCl₃) δppm: 1.40 (9H d, J = 4.5Hz), 1.65-1.9 (1H, m ), 2.0-2.25(1H, m), 3.05-3.4 (3H, m), 3.7-4.0 (1H, m), 4.6-4.8 (1H, m), 6.54 (2H,d, J = 8Hz), 6.65-6.8 (1H, m), 7.0- 7.25 (2H, m), 7.31 (1H, d, J = 7Hz),7.35-7.6 (3H, m), 7.75-8.0 (3H, m).

TABLE 17

Ref. Ex. No. R1 R2 R3 R4 R5 R6 NMR 151 —H —H —H —H —H

¹H-NMR (CDCl₃) δppm: 1.40 (9H, s), 175-2.0 (1H, m), 2.0-2.25 (1H, m),3.1- 3.4 (3H, m), 3.65-3.9 (1H, m), 4.45-4.65 (1H, m), 6.65 (2H, d, J =8Hz), 6.7-6.85 (2H, m), 7.00 (1H, dd, J = 2, 8,5Hz), 7.1-7.25 (2H, m),7.34 (1H, d, J = 2Hz), 7.50 (1H, dd, J = 3.5, 8.5Hz), 7.65 (1H, bs). 152—H —H —F —Cl —H

¹H-NMR (CDCl₃) δppm 1.40 (9H, s), 1.7-1.9 (1H, m), 2.1-2.3 (1H, m),3.1-3.4 (3H, m), 3.6-3.9 (1H, m), 4.3-4.5 (1H, m), 6.4-6.6 (1H, m), 6.64(1H, 6), 6.76 (1H, d, J = 7.4 Hz), 6.8-7.1 (2H, m), 7.31 (1H, s), 7.52(1H, dd, J = 8.9 Hz, J = 9.0 Hz), 7.67 (1H, s) 153 —H —H —F —Cl —H

¹H-NMR (CDCl₃) δppm 1.41 (9H, s), 1.7-1.9 (1H, m), 2.1-2.3 (1H, m),3.1-3.4 (3H, m), 3.6-3.8 (1H, m), 4.3-4.5 (1H, m), 6.5-6.7 (1H, m), 6.76(1H, d, J = 6.2 Hz), 6.9-7.1 (2H, m), 7.2-7.3 (1H, m), 7.4-7.6 (2H, m),7.8-7.9 (1H, m) 154 —H —H —H —H —H

¹H-NMR (CDCl₃) δppm: 1.41 (9H, s), 1.8-2.0 (1H, m), 2.0-2.25 (1H, m),3.1- 3.4 (3H, m), 3.65-3.95 (1H, m), 4.4-4.65 (1H, m), 6.82 (2H, dd, J =1, 8.5Hz), 6.95 (2H, dd, J = 2, 8.5Hz), 7.15-7.3 (3H, m), 7.36 (1H, d, J= 5.5Hz), 7.47 (1H, d, J = 2Hz), 7.73 (1H, dd, J = 2.5, 8.5Hz). 155 —H—H —H —H —H

¹H-NMR (CDCl₃) δppm: 1.41 (9H, s), 1.75-1.95 (1H, m), 2.0-2.25 (1H, m),3.1-3.4 (3H, m), 3.7-3.95 (1H, m), 4.5-4.75 (1H, m), 6.59 (2H, d, J =8Hz), 6.7-6.8 (1H, m), 7.05-7.25 (4H, m), 7.3-7.5 (2H, m), 7.86 (1H, d,J = 8Hz). 156 —H —H —H —H —H

¹H-NMR (CDCl₃) δppm: 1.40 (9H, s), 1.75-2.0 (1H, m), 2.0-2.25 (1H, m),3.1- 3.4 (3H, m), 3.7-3.9 (1H, m), 4.45-4.65 (1H, m), 6.76 (2H, d, J =8Hz), 6.89 (1H, dd, J = 7.5, 7.5Hz), 6.99 (1H, dd, J = 2.5, 8,5Hz),7.15-7.3 (3H, m), 7.4-7.5 (2H, m), 7.82 (1H, dd, J = 3.5, 8.5Hz). 157 —H—H —F —Cl —H

¹H-NMR (CDCl₃) δppm: 1.41 (9H, s), 1.75-2.0 (1H, m), 2.0-2.25 (1H, m),3.15-3.4 (3H, m), 3.65-3.9 (1H, m), 4.35-4.55 (1H, m), 6.55-6.7 (1H, m),6.82 (1H, dd, J = 3, 6.5Hz), 8.85-7.1 (2H, m), 7.30 (1H, d, J = 5.5Hz),7.41 (1H, d, J = 5.5Hz), 7.48 (1H, d, J = 2Hz), 7.76 (1H, d, J = 9Hz).

TABLE 18

Ref. Ex. No. R1 R2 R3 R4 R5 R6 NMR 158 —H —H —F —Cl —H

¹H-NMR (CDCl₃) δppm: 1.41 (9H, s), 1.68 (9H, s), 1.7-1.95 (1H, m),2.0-2.2 (1H, m), 3.1-3.3 (3H, m), 3.65-3.9 (1H, m), 4.4-4.6 (1H, m),6.26 (1H, d, J = 4Hz), 6.35-6.45 (1H, m), 6.60 (1H, dd, J = 3, 6Hz),6.8-6.95 (1H, m), 6.99 (1H, d, J = 7.5Hz), 7.25-7.4 (1H, m), 7.53 (1H,br), 8.15 (1H, d, J = 8.5Hz). 159 —H —H —F —Cl —H

¹H-NMR (CDCl₃) δppm: 1.41 (9H, s), 1.63 (9H, s), 1.8-2.0 (1H, m),2.0-2.25 (1H, m), 3.15-3.4 (3H, m), 3.65-3.85 (1H, m), 4.35- 4.45 (1H,m), 6.5-6.65 (2H, m), 6.6-6.8 (1H, m), 6.86 (1H, dd, J = 2, 8.5Hz),6.9-7.0 (1H, m), 7.45-7.55 (1H, m), 7.55-7.65 (1H, m), 7.88 (1H, br).160 —H —H —F —Cl —H

¹H-NMR (CDCl₃) δppm: 1.17 (18H, d, J = 7.5Hz), 1.40 (9H, s), 1.71 (3H,qq, J = 7.5, 7.5Hz), 1.75-1.95 (1H, m), 2.0-2.25 (1H, m), 3.05-3.35 (3H,m), 3.65-3.95 (1H, m), 4.4-4.6 (1H, m), 6.35-6.5 (1H, m), 6.6-6.75 (1H,m), 6.8-6.95 (1H, m), 7.0-7.3 (4H, m), 7.52 (1H, d, J = 8Hz). 161 —H —H—F —Cl —H

¹H-NMR (CDCl₃) δppm 1.42 (9H, s), 1.8-2.0 (1H, m), 2.1-2.3 (1H, m),3.2-3.5 (3H, m), 3.7-3.9 (1H, m), 4.4-4.6 (1H, m), 6.8-7.0 (1H, m),7.0-7.2 (2H, m), 7.4-7.8 (4H, m), 8.02 (1H, d, J = 8.2 Hz), 8.41 (1H, s)162 —H —H —F —Cl —H

¹H-NMR (CDCl₃) δppm 1.45 (9H, s), 1.90 (3H, s), 2.1-2.2 (1H m), 2.2-2.3(1H, m), 3.2-3.5 (3H, m), 3.8-4.0 (1H, m), 4.8-5.0 (1H, m), 6.8- 7.0(1H, m), 7.0-7.1 (2H, m), 7.3-7.5 (1H, m) 7.5-7.7 (2H, m), 7.76 (1H, d,J = 5.9 Hz), 7.9-8.0 (1H, m) 163 —H —H —F —Cl —H

¹H-NMR (CDCl₃) δppm: 1.39 (8H, d, J = 7.5Hz), 1.65-1.85 (1H, m),1.95-2.2 (1H, m), 3.05-3.35 (3H, m), 3.6-3.95 (1H, m), 4.5- 4.75 (1H,m), 6.25-8.4 (1H, m), 6.57 (1H, dd, J = 3, 6Hz), 6.75-7.0 (1H, m),7.3-7.45 (2H, m), 7.78 (1H, dd, J = 7.5. 7.5Hz), 8.05-8.25 (2H, m), 8.95(1H, d, J = 3.5Hz). 164 —H —H —H —H —H

¹H-NMR (CDCl₃) δppm: 1.39 (9H, d, J = 6Hz), 1.65-1.85 (1H, m), 1.86-2.25(1H, m), 3.05-3.35 (3H, m), 3.7-3.95 (1H, m), 4.6-4.8 (1H, m), 6.54 (2H,d, J = 8Hz), 6.65-6.8 (1H, m), 7.05-7.2 (2H, m), 7.3-7.45 (2H, m), 7.77(1H, d, J = 7.5, 7.5Hz), 8.1-8.25 (2H, m), 8.93 (1H, d, J = 3.5Hz). 165—H —H —F —Cl —H

¹H-NMR (CDCl₃) δppm 1.40 (9H, s), 1.7-1.9 (1H, m), 2.0-2.3 (1H, m),3.1-3.4 (3H, m), 3.7-3.9 (1H, m), 4.5-4.8 (1H, m), 6.3-6.5 (1H, m),6.5-6.7 (1H, m), 6.8-7.0 (1H, m), 7.5-7.8 (3H, m), 8.08 (1H, d, J = 6.7Hz), 8.37 (1H, s), 9.28 (1H, s)

TABLE 19

Ref. Ex. No. R1 R2 R3 R4 R5 R6 NMR 166 —H —H —H —H —H

¹H-NMR (CDCl₃) δppm 1.43 (9H, s), 1.8-2.0 (1H, m), 2.1-2.4 (1H, m),3.1-3.4 (3H, m), 3.7-3.9 (1H, m), 5.3-5.5 (1H, m), 7.0-7.1 (1H, m),7.2-7.4 (3H, m), 7.45 (1H, d, J = 7.7 Hz), 7.4-7.8 (3H, m), 7.61 (1H,dd, J = 8.2 Hz, J = 8.5 Hz) 167 —H —H —F —Cl —H

¹H-NMR (CDCl₃) δppm 1.44 (9H, s), 1.8-2.0 (1H, m), 2.2-2.4 (1H, m),3.2-3.5 (3H, m), 3.8-4.0 (1H, m), 5.2-5.4 (1H, m), 7.0-7.4 (4H, m), 7.40(1H, d, J = 8.6 Hz), 7.50 (1H, d, J = 7.7 Hz), 7.62 (1H, dd, J = 8.2 Hz,J = 8.6 Hz) 168 —H —H —F —Cl —H

¹H-NMR (CDCl₃) δppm 1.43 (9H, s), 1.8-2.0 (1H, m), 2.2-2.4 (1H, m),3.2-3.5 (3H, m), 3.80 (3H, s), 3.8-4.0 (1H, m), 5.2-5.4 (1H, m), 6.32(1H, d, J = 8.6 Hz), 7.03 (1H, s), 7.1-7.3 (2H, m), 7.39 (1H, d, J = 8.6Hz), 7.52 (1H, dd, J = 9.0 Hz, J = 9.0 Hz) 169 —H —H —F —Cl —H

¹H-NMR (CDCl₃) δppm 1.44 (9H, s), 1.9-2.1 (1H, m), 2.1-2.3 (1H, m),3.2-3.4 (3H, m), 3.7-3.9 (1H, m), 4.6-4.8 (1H, m), 6.77 (1H, d, J = 5.6Hz), 7.1-7.2 (2H, m), 7.29 (1H, d, J = 6.4 Hz), 7.37 (1H, d, J = 5.6Hz), 7.45 (1H, d, J = 5.6 Hz), 3.49 (1H, d, J = 5.6 Hz) 170 —H —H —H —F—H

¹H-NMR (CDCl₃) δppm 1.43 (9H, s), 1.82-2.00 (1H, m), 2.03-2.25 (1H, m),3.10- 3.39 (3H, m), 4.32-4.50 (1H, m), 6.37 (1H, dt, J = 2.3Hz and12.2Hz), 6.41-6.57 (2H, m), 3.76 (1H, dd, J = 1.4Hz and J = 5.1Hz), 6.96(1H, dd, J = 1.4Hz and J = 3.1Hz), 7.06-7.18(1 H, m... 171 —H —H —F —Cl—H

¹H-NMR (CDCl₃) δppm 1.11 (18H, d, J = 7.4Hz), 1.43 (9H, s), 1.77-2.21(2H, m), 3.07-3.35 (3H, m), 3.59-3.82 (1H, m), 4.26-4.42 (1H, m),5.97-6.02 (1H, m), 6.43-6.58 (2H, m), 6.62-6.70 (1H, m), 6.76 (1H, s),6.83-6.95 (1H, m)

TABLE 20

Ref. Ex. No. R1 R2 R3 R4 R5 R6 NMR 172 —H —H —Cl —Cl —H

¹H-NMR (CDCl₃) δppm 1.42(9H, s), 1.81-2.011(1H, m), 2.03-2.31(1H, m),2.23(3H, d, J = 1.0Hz), 3.12-3.38(3H, m), 3.69-3.85(1H, m),4.89-5.01(1H, m), 6.85(1H, brs), 7.11(1H, dd, J = 2.5Hz, 8.5Hz),7.37(1H, d, J = 2.5Hz), 7.51- 7.54(1H, m) 173 —H —H —F —Cl —H

¹H-NMR (CDCl₃) δppm 1.43 (9H, s), 1.81-2.00 (1H, m), 2.10-2.40 (1H, m),3.11- 3.41 (3H, m), 3.68-3.88 (1H, m), 4.99-5.13 (1H, m), 6.51 (1H, d, J= 3.5Hz), 7.12-7.31 (3H, m), 7.35 (1H, dd, J = 6.5Hz and J = 2.5Hz) 174—H —H —Cl —Cl —H

¹H-NMR (CDCl₃) δppm 1.43(9H, s), 1.83-2.03(1H, m), 2.11-2.35(1H, m),3.18- 3.42(3H, m), 3.73-3.87(1H, m), 4.97-5.09(1H, m), 6.53(1H, d, J =3.5Hz), 7.14(1H, dd, J = 2.5Hz, 8.5Hz), 7.22(1H, brs), 7.39(1H, d, J =2.5Hz), 7.56(1H, brd, J = 8.5Hz) 175 —H —H —F —Cl —H

¹H-NMR (CDCl₃) δppm 1.42(9H, s), 1.80-2.03(1H, m), 2.08-2.22(1H, m),2.22(3H, s), 3.13-3.38(3H, m), 3.68-3.85(1H, m), 4.98(1H, tt, J = 6.5Hz,6.5Hz), 6.84(1H, brs), 7.11- 7.23(2H, m), 7.33(1H, dd, J = 2.5Hz, 6.5Hz)176 —H —H —F —H —H

¹H-NMR (CDCl₃) δppm 1.42(9H, s), 1.78-2.03(1H, m), 2.08-2.33(1H, m),3.08- 3.42(3H, m), 3.71-3.87(1H, m), 5.03-5.20(1H, m), 6.47(1H, d, J =3.5Hz), 7.11-7.32(5H, m) 177 —H —H —F —Cl —H

¹H-NMR (CDCl₃) δppm 1.43 (9H, s), 1.80-2.00 (1H, m), 2.10-2.31 (1H, m),3.18- 3.42 (3H, m), 3.63-3.80 (1H, m), 4.38-4.50 (1H, m), 6.95- 7.05(1H,m), 7.14-7.30 (2H, m with dd at δ7.17, J = 2.6Hz and 6.4Hz), 8.12 (2H,s), 3.72 (1H, s) 178 —H —H —F —Cl —H

¹H-NMR (CDCl₃) δppm 1.44 (9H, s), 1.70-1.90 (1H, m), 2.02-2.21 (1H, m),3.09- 3.41 (3H, m), 3.75-3.90 (1H, m), 5.21-5.38 (1H, m), 6.62 (1H, s),6.99-7.09 (1H, m), 7.15-7.29 (2H, m), 8.21- 8.41 (2H, m) 179 —H —H —F—Cl —H

¹H-NMR (CDCl₃) δppm 1.43 (9H, s), 1.7-1.9 (1H, m), 2.1-2.3 (1H, m), 2.53(3H, s), 3.1-3.4 (3H, m), 3.7-3.9 (1H, m), 5.3-5.5 (1H, m), 5.56 (1H, d,J = 5.7 Hz), 7.0-7.1 (1H, m), 7.2-7.3 (2H, m), 7.91(1H, d, J = 5.7 Hz)

TABLE 21

Ref. Ex. No. R1 R2 R3 R4 R5 R6 NMR 180 —H —H —F —Cl —H

¹H-NMR (CDCl₃) δppm 1.43 (9H, s), 1.71-1.90 (1H, m), 2.01-2.25 (1H, m),3.08-3.40 (3H, m), 3.71-3.89 (1H, m), 5.12-5.39 (1H, m), 7.05-7.13 (1H,m), 7.23-7.33(2H, m), 7.49 (1H, s), 7.00 (1H, s), 8.09 (1H, s) 181 —H —H—F —H —H

¹H-NMR (CDCl₃) δppm 1.43 (9H, s), 1.69-1.87 (1H, m), 2.00-2.21 (1H, m),3.05-3.34 (3H, m), 3.71-3.87 (1H, m), 5.13-5.27 (1H, m), 7.17 (4H, d, J= 5.5Hz), 7.44 (1H, s), 7.85 (1H, s). 8.08 (1H, s). 182 —H —H —F —Cl —H

¹H-NMR (CDCl₃) δppm 1.40 (9H, s), 1.8-1.9 (1H, m), 2.0-2.2 (1H, m),3.1-3.4 (3H, m), 3.6-3.8 (1H, m), 4.2-4.4 (1H, m), 6.5-6.6 (1H, m), 6.62(1H, dd, J = 10.0 Hz, J = 9.8 Hz), 6.72 (1H, d, J = 6.0 Hz), 6.9-7.1(1H, m), 7.2-7.3 (2H, m), 13.17 (1H, brs) 183 —H —H —F —Cl —H

¹H-NMR (CDCl₃) δppm 1.44 (9H, s), 1.7-1.9 (1H, m), 2.0-2.2 (1H, m),3.0-3.4 (3H, m), 3.6-3.8 (1H, m), 4.2-4.4 (1H, m), 4.9-5.3 (2H, m),6.4-6.5 (1H, m), 6.6-6.7 (2H, m), 6.7-7.1 (3H, m), 7.2-7.4 (5H, m)

TABLE 22

Ref. Ex. No. R1 NMR 184

¹H-NMR (CDCl₃) δppm: 1.47 (9H, s), 2.04 (1H, br), 2.15-2.35 (1H, m),3.2-3.4 (1H, m), 3.4-3.6 (2H, m), 3.65-3.95 (2H, m), 4.17 (1H, br), 6.81(1H, d, J = 2.3Hz), 6.86 (1H, dd, J = 2.4, 8.7Hz), 7.15-7.3 (1H, m),7.37 (1H, dd, J = 7.8, 7.8Hz), 7.56-7.7 (3H, m). 185

¹H-NMR (CDCl₃) δppm: 1.47 (9H, s), 1.91 (1H, br), 2.1-2.3 (1H, m),3.1-3.35 (1H, m), 3.35-3.85 (4H, m), 4.05 (1H, br), 6.55-6.7 (2H, m),6.77 (1H, d, J = 2.3Hz), 7.31 (1H, d, J = 8.8Hz), 7.54 (1H, d, J =2.0Hz). 186

¹H-NMR (CDCl₃) δppm: 1.47 (9H, s), 1.93 (1H, br), 2.15-2.3 (1H, m),3.15-3.4 (1H, m), 3.4-3.6 (2H, m), 3.65-3.85 (1H, m), 3.85-4.0 (1H m),4.0-4.2 (1H, m), 6.75 (1H, dd, J = 2.1, 8.7Hz), 6.9-7.0 (2H, m), 7.60(1H, d, J = 8.6Hz). 187

¹H-NMR (CDCl₃) δppm: 1.47 (9H, s), 1.85-2.05 (1H, m), 2.15-2.35 (1H, m),3.2-3.4 (1H, m), 3.4-3.6 (2H, m), 3.65-3.9 (2H, m), 4.16 (1H, br), 6.76(1H, dd, J = 2.2, 8.5Hz), 6.96 (1H, d, J = 2.3Hz), 7.26 (1H, s), 7.59(1H, d, J = 8.6Hz). 188

¹H-NMR (CDCl₃) δppm: 1.47 (9H, s), 1.85-2.0 (1H, m), 2.1-2.3 (1H, m),2.36 (3H, d, J = 1.1Hz), 3.1-3.35 (1H, m), 3.4-3.6 (2H, m), 3.65-3.85(2H, m), 4.0-4.2 (1H, m), 6.71 (1H, dd, J = 2.2, 8.6Hz), 6.76 (1H, d, J= 0.8Hz), 7.01 (1H, d, J = 2.1Hz), 7.49 (1H, d, J = 8.6Hz). 189

¹H-NMR (CDCl₃) δppm: 1.47 (9H, s), 1.85-2.0 (1H, m), 2.15-2.3 (1H, m),2.37 (3H, s), 3.15-3.35 (1H, m), 3.4-3.6 (2H, m), 3.65-3.85 (2H, m),4.05-4.25 (1H, m), 6.72 (1H, dd, J = 2.2, 8.6Hz), 6.85 (1H, d, J =2.1Hz), 7.03 (1H, s), 7.61 (1H, d, J = 8.5Hz). 190

¹H-NMR (CDCl₃) δppm: 1.65 (9H, s), 2.04 (1H, br), 2.1-2.3 (1H, m),3.15-3.35 (1H, m), 3.35-3.8 (2H, m), 3.6-3.8 (1H, m), 3.8-3.95 (1H, m),3.95-4.1 (1H, m), 6.71 (1H, d, J = 1.9Hz), 6.90 (1H, d, J = 1.5Hz), 7.15(1H, d, J = 5.5Hz), 7.30 (1H, d, J = 5.7Hz). 191

¹H-NMR (CDCl₃) δppm: 1.47 (9H, s), 1.9-2.1 (1H, m), 2.05-2.35 (1H, m),3.2-3.65 (3H, m), 3.65-3.9 (1H, m), 4.0-4.3 (2H, m), 6.53 (1H, d, J =7.4Hz), 7.15-7.4 (4H, m). 192

¹H-NMR (CDCl₃) δppm: 1.47 (9H, s), 1.91 (1H, br), 2.0-2.3 (1H, m), 2.51(3H, d, J = 0.9Hz), 3.15-3.35 (1H, m), 3.35-3.6 (2H, m), 3.6-3.85 (2H,m), 4.07 (1H, br), 6.62 (1H, dd, J = 2.2, 8.5Hz), 6.80 (1H, s), 6.93(1H, d, J = 2.1Hz), 7.42 (1H, d, J = 8.5Hz).

TABLE 23

Ref. Ex. No. R1 NMR 193

¹H-NMR (CDCl₃) δppm: 1.47 (9H, s), 1.97 (1H, br), 2.15-2.3 (1H, m),3.15-3.4 (1H, m), 3.4-3.6 (2H, m), 3.65-3.85 (1H, m), 4.0-4.25 (2H, m),6.70 (1H, dd, J = 2.0, 8.7Hz), 6.96 (1H, d, J = 1.5Hz), 7.79 (1H, d, J =8.7Hz), 8.65 (1H, s). 194

¹H-NMR (CDCl₃) δppm: 1.47 (9H, s), 1.8-2.0 (1H, m), 2.15-2.35 (1H, m),3.15-3.6 (3H, m), 3.7-3.85 (1H, m), 4.4-4.65 (2H, m), 6.43 (1H, d, J =8.6Hz), 7.07 (2H, s), 7.76 (1H, d, J = 8.6Hz). 195

¹H-NMR (CDCl₃) δppm: 1.47 (9H, s), 1.93 (1H, br), 2.17-2.29 (1H, m),3.27 (1H, br), 3.49 (2H, br), 3.69 (3H, s) 3.92 (2H, br), 4.08 (1H, br),6.69 (1H, d, J = 9.6 Hz), 6.71 (1H, d, J = 2.9 Hz), 6.91 (1H, dd, J =9.0 Hz), 7.23 (1H, d, J = 2.9, 9.0 Hz), 7.55 (1H, d, J = 9.6Hz).

TABLE 24

Ref. Ex. No. R1 R2 R3 R4 R5 NMR 196 —H —H —F —F —H ¹H-NMR (CDCl₃)δppm:1.47(9H, s), 1.76-1.95(1H, m), 2.09- 2.25(1H, m), 3.11-3.32(1H, m),3.36-3.56 (2H, m), 3.58- 3.78(2H, m), 3.85-4.03(1H, m), 6.19-6.30(1H,m), 6.34-6.43(1H, m), 6.96 (1H, dd, J = 9.0, 19.0Hz) 197 —H —Cl —H —Cl—H ¹H-NMR (CDCl₃) δppm: 1.47 (9H, s), 1.77-1,95 (1H, m), 2.02- 2.27 (1H,m), 3.15-3.75 (3H, m), 3.87-4.02 (2H, m), 6.45-6.46 (2H, m), 6.68-6.70(1H, m). 198 —H —H —Cl —CH₃ —H ¹H-NMR (DMSO-d₆) δppm: 1.39 (9H, s),1.64-1.85 (1H, m), 2.00-2.18 (1H, m), 2.21 (3H, s), 2.97-3.10 (1H, m),3.22-3.39 (2H, m), 3.42-3.60 (1H, m), 3.78-3.96 (1H, m), 5.89 (1H, d, J= 6.8 Hz), 6.43 (1H, dd, J = 8.6, 2.5 Hz), 6.55 (1H, d, J = 2.5 Hz),7.06 (1H, d, J = 8.6 Hz). 199 —H —OCH₃ —F —F —H ¹H-NMR (DMSO-d₆) δppm:1.39 (9H, s), 1.60-1.82 (1H, m), 1.93-2.17 (1H, m), 2.92-3.10 (1H, m),3.20-3.44 (1H, m), 3.48- 3.57 (1H, m), 3.75 (3H, s), 3.80-4.00 (1H, m),6.01-6.19 (2H, m). 200 —H —F —F —F —H ¹H-NMR (CDCl₃) δppm: 1.47 (9H, s),1.74-1.92 (1H, m), 2.08- 2.21 (1H, m), 3.08-3.28 (1H, m), 3.33-3.51 (2H,m), 3.61-3.96 (2H, m), 6.08-6.21 (2H, m). 201 —H —F —Cl —F —H ¹H-NMR(CDCl₃) δppm: 1.45 (9H, s), 1.78-1.93(1H, m), 2.03- 2.24 (1H, m),3.09-3.31 (1H, m), 3.36-3.52 (2H, m), 3.60-3.75 (1H, m), 3.85-4.08 (1H,m), 6.15-6.24 (2H, m). 202 —H —H —CH₃ —F —H ¹H-NMR (CDCl₃) δppm: 1.46 (9H, s), 1.87 (1H, br ), 2.14-2.23 (1H, m), 2.15 (3H, d, J = 1.4 Hz),3.21 (1H, br), 3.45 (2H, br), 3.68 (2H, br ), 3.97 (1H, br), 6.26-6.31(2H, m), 6.95 (1H, dd, J = 8.5, 10.7 Hz). 203 —H —H —Cl —H —H ¹H-NMR(CDCl₃) δppm 1.46 (9H, s), 1.78-1.96 (1H, m), 2.10- 2.20(1H, m),3.11-3.30 (1H, m), 3.40-3.56 (2H, m), 3.60- 3.80(2H, m), 3.85-4.03 (1H,m), 6.52 (2H, d, J = 8.7Hz), 7.12 (1H, d, 8.7Hz)

TABLE 25

Ref. Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 NMR 204 —H —H —F —Cl —H —CH₃—H —F —H —H ¹H-NMR (CDCl₃) δppm; {1.42 (s), 1.44 (s) total 9H, 1:1},1.71-1.89 (1H, m), 2.03-2.19 (1H, m), 2.08 (3H, s), 3.12- 3.36 (3H, m),3.61-3.82 (1H, m), 4.32- 4.45 (1H, m), 6.23-6.29 (1H, m), 6.46 (1H, dd,J = 3.0, 6.0 Hz), 6.86-7.07 (4H, m) 205 —H —H —F —F —H —H —F —F —H —H¹H-NMR (CDCl₃) δppm; 1.43 (9H, s), 1.73-1.92 (1H, m), 2.00-2.22 (1H, m),3.11-3.36 (3H, m), 3.59-3.78 (1H, m), 4.25-4.41 (1H, m), 6.51-6.72 (4H,m), 7.09 (2H, dd, J = 8.5, 18.0 Hz)

TABLE 26

Ref. Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 NMR 206 —H —Cl —Cl —H —H —H —H—H —H ¹H-NMR (CDCl₃) δppm; 1.43 (9H, s), 1.79-1.90 (1H, m), 2.10-2.20(1H, m), 3.15-3.33 (3H, m), 3.67-3.84 (1H, m), 4.39-4.52 (1H, m), 6.63(1H, dd, J = 2.7, 8.8 Hz), 6.89 (1H, d, J = 2.7 Hz), 7.24-7.32 3H, m),8.28 (1H, brs), 8.42 (1H, brs). 207 —H —Cl —F —H —H —H —H —H —CH₃ ¹H-NMR(CDCl₃) δppm; 1.44 (9H, s), 1.74-1.89 (1H, m), 2.04-2.20 (1H, m), 2.12(3H, s), 3.13-3.21 (1H, m), 3.24-3.38 (2H, m), 3.69-3.85 (1H, m),4.39-4.55 (1H, m), 6.25-6.36 (1H, m), 6.52 (1H, dd, J = 3.1, 6.0 Hz),6.90-6.98 (1H, m), 7.25-7.28 (1H, m), 8.30 (1H, s), 8.48 (1H, d, J = 4.8Hz). 208 —H —Cl —Cl —H —H —H —H —H —CH₃ ¹H-NMR (CDCl₃) δppm; 1.43 (9H,s), 1.70-1.86 (1H, m), 2.04-2.28 (1H, m), 2.12 (3H, s), 3.14-3.21 (1H,m), 3.23-3.35 (2H, m), 3.68-3.84 (1H, m), 4.43-4.51-5.35 (1H, m), 6.29(1H, d, 8.7 Hz), 6.56 (1H, d, J = 2.9 Hz), 7.16-7.20 (1H, m), 7.27-7.30(1H, m), 8.29 (1H, s), 8.50 (1H, d, J = 4.7 Hz).

TABLE 27

Ref. Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 NMR 209 —H —Cl —H —Cl —H —H —H—H —H ¹H-NMR (CDCl₃) δppm: 1.43 (9H, s), 1.72-1.89 (1H, m), 2.08-2.24(1H, m), 3.09-3.32 (3H, m), 3.67-3.84 (1H, m), 4.38-4.52 (1H, m),6.52-6.53 (2H, m), 6.87-6.89 (1H, m), 7.35-7.40 (2H, m), 8.34-8.35 (1H,m), 8.54-8.56 (1H, m). 210 —H —CH₃ —Cl —H —H —H —H —H —H ¹H-NMR (CDCl₃)δppm: 1.43 (9H, s), 1.79-1.92 (1H, m), 2.04-2.22 (1H, m), 2.34 (3H, s),3.15-3.38 (3H, m), 6.76 (1H, dd, J = 8.4, 2.5 Hz), 6.85 (1H, d, J = 2.5Hz), 6.97-7.05 (1H, m), 6.87-6.89 (1H, dd, J = 8.4, 4.6 Hz), 7.27-7.35(1H, m), 8.09-8.145 (1H, m), 8.18 (1H, d, J = 3.8 Hz). 211 —H —Cl —F —H—H —H —H —F —H ¹H-NMR (CDCl₃) δppm: 1.43 (9H, s), 1.8-1.95 (1H, m),2.05-2.3 (1H, m), 3.15-3.4 (3H, m), 3.65-3.8 (1H, m), 4.35-4.5 (1H, m),6.59 (1H, d, J = 10.2 Hz), 6.95-7.05 (1H, m), 7.1-7.3 (2H, m), 7.84 (1H,br), 7.96 (1H, d, J = 2.1 Hz). 212 —H —CH₃ —F —H —H —H —H —F —H ¹H-NMR(CDCl₃) δppm: 1.43 (9H, s), 1.8-1.95 (1H, m), 2.05-2.25 (1H, m), 2.29(3H, s), 3.15- 3.35 (3H, m), 3.65-3.8 (1H, m), 4.35-4.5 (1H, m),6.45-6.55 (1H, m), 6.85-6.95 (2H, m), 7.0- 7.15 (1H, m), 7.79 (1H, br),7.87 (1H, d, J = 1.9 Hz). 213 —H —H —F —H —H —H —H —F —H ¹H-NMR (CDCl₃)δppm: 1.43 (9H, s), 1.8-1.95 (1H, m), 2.05-2.25 (1H, m), 3.1-3.35 (3H,m), 3.65-3.8 (1H, m), 4.35-4.5 (1H, m), 6.45-6.55 (1H, m), 7.05-7.2 (4H,m), 7.80 (1H, br), 7.88 (1H, d, J = 2.1 Hz).

TABLE 28

Ref. Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 NMR 214 —H —Cl —F —H —H —H —H —F—H ¹H-NMR (CDCl₃) δppm: 1.43 (9H, s), 1.8-1.95 (1H, m), 2.05-2.3 (1H,m), 3.15-3.4 (3H, m), 3.65-3.8 (1H, m), 4.35-4.5 (1H, m), 6.59 (1H, d, J= 10.2 Hz), 6.95-7.05 (1H, m), 7.1-7.3 (2H, m), 7.84 (1H, br), 7.96 (1H,d, J = 2.1 Hz). 215 —H —CH₃ —F —H —H —H —H —F —H ¹H-NMR (CDCl₃) δppm:1.43 (9H, s), 1.8-1.95 (1H, m), 2.05-2.25 (1H, m), 2.29 (3H, s), 3.15-3.35 (3H, m), 3.65-3.8 (1H, m), 4.35-4.5 (1H, m), 6.45-6.55 (1H, m),6.85-6.95 (2H, m), 7.0- 7.15 (1H, m), 7.79 (1H, br), 7.87 (1H, d, J =1.9 Hz). 216 —H —H —F —H —H —H —H —F —H ¹H-NMR (CDCl₃) δppm: 1.43 (9H,s), 1.8-1.95 (1H, m), 2.05-2.25 (1H, m), 3.1-3.35 (3H, m), 3.65-3.8 (1H,m), 4.35-4.5 (1H, m), 6.45-6.55 (1H, m), 7.05-7.2 (4H, m), 7.80 (1H,br), 7.88 (1H, d, J = 2.1 Hz).

TABLE 29

Ref. Ex. No. R1 R2 R3 R4 R5 R6 NMR 217 —H —H —Cl —Cl —H

¹H-NMR (CDCl₃) δppm: 1.43 (9H, s), 1.75-1.89 (1H, m), 2.03-2.20 (1H, m),3.08-3.33 (3H, m), 3.80 (1H, dd, J = 7.1, 10.9 Hz), 5.17-5.29 (1H, m),6.00 (1H, d, J = 9.0 Hz), 7.03 (1H, dd, J = 2.4, 8.4 Hz), 7.25 (1H, dd,J = 2.2, 9.0 Hz), 7.29 (1H, d, J = 2.2 Hz), 7.52-7.57 (1H, dd, J = 4.7,8.3 Hz), 8.13 (1H, d, J = 4.7 Hz). 218 —H —H —F —Cl —H

¹H-NMR (CDCl₃) δppm: 1.44 (9H, s), 1.80-2.21 (2H, m), 3.20-3.47 (3H, m),3.57-3.78 (1H, m), 4.68-4.74 (1H, m), 6.85-7.03 (4H, m), 7.55-7.59 (1H,m), 8.29-8.32 (1H, m). 219 —H —H —F —Cl —H

¹H-NMR (CDCl₃) δppm: 1.44 (9H, s), 1.71-1.89 (1H, m), 2.04-2.28 (1H, m),3.10-3.34 (3H, m), 3.85 (1H, dd, J = 7.5, 10.3 Hz), 5.35-5.43 (1H, m),6.08 (1H, d, J = 8.8 Hz), 7.07-7.12 (1H, m), 7.26- 7.36 (5H, m),7.46-7.51 (2H, m), 8.42 (1H, d, J = 5.9 Hz). 220 —H —H —F —Cl —H

¹H-NMR (CDCl₃) δppm: 1.43 (9H, s), 1.80-1.93 (1H, m), 2.05-2.21 (1H, m),3.14-3.35 (3H, m), 3.67-3.82 (1H, m), 4.35-4.46 (1H, m), 5.36 (1H, d, J= 10.8 Hz), 6.05 (1H, d, J = 17.4 Hz), 6.75 (1H, dd, J = 10.8, 17.4 Hz),6.83-6.89 (1H, m), 7.02-7.19 (3H, m), 7.24 (1H, d, J = 8.6 Hz), 8.09(1H, s). 221 —H —H —Cl —Cl —H

¹H-NMR (CDCl₃) δppm: 1.32 (9H, s), 1.75-1.89 (1H, m), 2.08-2.20 (1H, m),3.07-3.32 (3H, m), 3.67-3.81 (1H, m), 3.97 (3H, s), 4.38-4.46 (1H, m),6.42 (1H, dd, J = 2.9, 9.0 Hz), 6.66 (1H, d, J = 2.9 Hz), 6.81 (1H, dd,J = 3.1, 8.4 Hz), 7.17 (1H, d, J = 6.8 Hz), 7.30 (1H, dd, J = 2.7, 8.8Hz), 7.94 (1H, d, 2.3 Hz). 222 —H —H —F —Cl —H

¹H-NMR (CDCl₃) δppm: 1.43 (9H, s), 1.80-1.93 (1H, m), 2.15-2.20 (1H, m),2.29 (3H, s), 3.18- 3.39 (3H, m), 3.63-3.77 (1H, m), 4.41 (1H, brs),6.85-6.91 (2H, m), 7.03-7.07 (1H, m), 7.11-7.18 (1H, m), 7.73 (1H, brs).223 —H —H —F —Cl —H

¹H-NMR (CDCl₃) δppm: 1.43 (9H, s), 1.78-1.92 (1H, m), 2.09-2.36 (1H, m),2.55 (3H, s), 3.15- 3.32 (3H, m), 3.68-3.99 (1H, m), 5.31-5.52 (1H, m),6.24 (1H, d, J = 9.2 Hz), 6.96 (1H, d, J = 9.2 Hz), 7.06 (1H, ddd, J =2.6, 4.2, 8.6 Hz), 7.15- 7.27 (1H, m), 7.55-7.59 (1H, m). 224 —H —H —F—Cl —H

¹H-NMR (CDCl₃) δppm: 1.43 (9H, s), 1.78-1.97 (1H, m), 2.08-2.36 (1H, m),3.12-3.32 (3H, m), 3.67-3.96 (1H, m), 4.05 (3H, s), 5.14-5.33 (1H, m),6.39 (1H, d, J = 9.6 Hz), 6.72 (1H, d, J = 9.6 Hz), 7.07 (1H, ddd, J =2.6, 4.2, 8.6 Hz), 7.11- 7.32 (2H, m).

TABLE 30

Ref. Ex. No. R1 R2 R3 R4 R5 R6 NMR 225 —H —H —F —Cl —H

¹H-NMR (CDCl₃) δppm: 1.43 (9H, s), 1.81-1.95 (1H, m), 2.10-2.35 (1H, m),3.12-3.30 (3H, m), 3.74-3.95 (1H, m), 5.34-5.45 (1H, m), 6.31 (1H, d, J= 9.4 Hz), 7.06-7.10 (2H, m), 7.21-7.33 (2H, m). 226 —H —H —F —Cl —H

¹H-NMR (CDCl₃) δppm: 1.43 (9H, s), 1.84-1.99 (1H, m), 2.10-2.29 (1H, m),3.12-3.38 (3H, m), 3.70-3.76 (1H, m), 4.36-4.45 (1H, m), 7.02 (1H, ddd,J = 2.7, 4.1, 8.6 Hz), 7.20 (1H, dd, J = 2.5, 6.4 Hz), 7.21-7.28 (1H,m), 7.97 (2H, m). 227 —H —H —F —Cl —H

¹H-NMR (CDCl₃) δppm: 1.44 (9H, s), 1.80-1.95 (1H, m), 2.04-2.20 (1H, m),3.20-3.40 (3H, m), 3.70 (6H, s), 3.77-3.88 (1H, m), 5.21-5.30 (1H, m),5.46 (1H, s), 7.02 (1H, ddd, J = 2.5, 4.3, 8.7 Hz), 7.13-7.19 (1H, m),7.24 (1H, dd, J = 2.4, 6.6 Hz). 228 —H —H —F —Cl —H

¹H-NMR (CDCl₃) δppm: 1.43 (9H, s), 1.70-1.88 (1H, m), 1.97-2.20 (1H, m),3.07-3.30 (3H, m), 3.72-3.82 (1H, m), 3.83 (3H, s), 3.96 (3H, s), 4.86(1H, s), 5.37-5.41 (1H, m), 7.05 (1H, ddd, J = 2.6, 4.2, 8.7 Hz),7.21-7.31 (2H, m). 229 —H —H —F —H —H

¹H-NMR (CDCl₃) δppm: 1.43 (9H, s), 1.86-1.96 (1H, m), 2.16-2.28 (1H, m),3.10-3.35 (3H, m), 3.72-3.77 (1H, m), 4.41-4.51 (1H, m), 7.09-7.17 (4H,m), 8.07 (2H, s), 8.64 (1H, s). 230 —H —H —F —CH₃ —H

¹H-NMR (CDCl₃) δppm: 1.43 (9H, s), 1.85-1.97 (1H, m), 2.05-2.28 (1H, m),2.29 (3H, s), 3.20- 3.35 (3H, m), 3.70-3.78 (1H, m), 4.43-4.47 (1H, m),6.89-7.97 (2H, m), 7.06-7.13 (1H, m), 8.06 (2H, s), 8.63 (1H, s). 231 —H—H —Cl —Cl —H

¹H-NMR (CDCl₃) δppm: 1.43 (9H, s), 1.81-1.96 (1H, m), 2.10-2.31 (1H, m),3.15-3.39 (3H, m), 3.63-3.78 (1H, m), 4.37-4.45 (1H, m), 6.90 (1H, dd, J= 2.5, 8.6 Hz), 7.16 (1H, d, J = 2.4 Hz), 7.51 (1H, d, J = 8.3 Hz), 8.05(2H, s). 232 —H —H —F —H —H

¹H-NMR (CDCl₃) δppm: 1.42 (9H, s), 1.78-1.93 (1H, m), 2.10-2.26 (1H, m),3.09-3.37 (3H, m), 3.63-3.70 (1H, m), 4.37-4.45 (1H, m), 7.07-7.29 (4H,m), 7.92 (2H, s). 233 —H —H —F —CH₃ —H

¹H-NMR (CDCl₃) δppm: 1.43 (9H, s), 1.81-1.95 (1H, m), 2.05-2.27 (1H, m),2.29 (3H, s), 3.19- 3.43 (3H, m), 3.65-3.80 (1H, m), 4.35-4.43 (1H, m),6.90-6.97 (2H, m), 7.07-7.13 (1H, m), 7.91 (2H, s).

TABLE 31

Ref. Ex. No. R1 R2 R3 R4 R5 R6 NMR 234 —H —H —F —Cl —H

¹H-NMR (CDCl₃) δppm: 1.44 (9H, s), 1.74-1.90 (1H, m), 2.08-2.26 (1H, m),3.09-3.35 (3H, m), 3.78- 3.88 (1H, m), 5.20-5.35 (1H, m), 6.92 (1H, d, J= 4.8 Hz), 7.04 (1H, ddd, J = 2.5, 4.2, 8.7 Hz), 7.20- 7.25 (2H, m),8.47 (1H, d, J = 4.6 Hz). 235 —H —H —Cl —Cl —H

¹H-NMR (CDCl₃) δppm: 1.43 (9H, s), 1.77-1.88 (1H, m), 2.05-2.28 (1H, m),2.52 (3H, s), 3.15-3.33 (3H, m), 3.70-3.90 (1H, m), 5.28-5.43 (1H, m),5.60 (1H, d, J = 6.0 Hz), 7.03 (1H, dd, J = 2.4, 8.5 Hz), 7.29 (1H, d, J= 2.4 Hz), 7.58 (1H, d, J = 8.3 Hz), 7.90 (1H, d, J = 6.0 Hz). 236 —H —H—Cl —Cl —H

¹H-NMR (CDCl₃) δppm: 1.44 (9H, s), 1.75-1.88 (1H, m), 2.05-2.20 (1H, m),3.12-3.36 (3H, m), 3.77- 3.87 (1H, m), 5.24-5.34 (1H, m), 6.62 (1H,brs), 7.02 (1H, dd, J = 2.4, 8.5 Hz), 7.27 (1H, d, J = 2.4 Hz), 7.51(1H, dd, J = 4.1, 8.4 Hz), 8.32 (2H, brs). 237 —H —H —F —Cl —H

¹H-NMR (CDCl₃) δppm: 1.44 (9H, s), 1.87-1.96 (1H, m), 2.04-2.20 (1H, m),3.15-3.39 (3H, m), 3.61 (3H, s), 3.72-3.84 (1H, m), 4.77-4.86 (1H, m),6.96 (1H, ddd, J = 2.6, 4.3, 8.7 Hz), 7.06 (1H, dd, J = 2.6, 8.5 Hz),7.11 (1H, dd, J = 2.6, 6.6 Hz), 7.65 (1H, brs), 7.79 (1H, d, J = 4.4Hz). 238 —H —H —F —Cl —H

¹H-NMR (CDCl₃) δppm: 1.42 (9H, s), 1.90-2.20 (2H, m), 2.00 (3H, s), 2.48(3H, s), 3.22-3.45 (3H, m), 3.61-3.82 (1H, m), 4.67-4.76 (1H, m),6.80-6.84 (1H, m), 6.95-7.02 (1H, m), 7.08 (1H, t, J = 8.6 Hz), 8.04(1H, d, J = 5.2 Hz). 239 —H —H —F —Cl —H

¹H-NMR (CDCl₃) δppm: 1.44 (9H, s), 1.78-1.86 (1H, m), 2.05-2.24 (1H, m),3.08-3.31 (3H, m), 3.80 (1H, dd, J = 7.0, 9.0 Hz), 5.17-5.23 (1H, m),7.10 (1H, ddd, J = 2.6, 3.9, 8.7 Hz), 7.26-7.32 (3H, m), 7.88 (1H, s).240 —H —H —Cl —Cl —H

¹H-NMR (CDCl₃) δppm: 1.44 (9H, s), 1.77-1.87 (1H, m), 2.04-2.21 (1H, m),3.11-3.35 (3H, m), 3.75- 3.86 (1H, m), 5.14-5.23 (1H, m), 7.07 (1H, dd,J = 2.4, 8.5 Hz), 7.33 (1H, d, J = 2.4 Hz), 7.51 (1H, d, J = 1.1 Hz),7.58 (1H, dd, J = 3.9, 8.2 Hz), 7.90 (1H, s), 8.09 (1H, s). 241 —H —H—Cl —Cl —H

¹H-NMR (CDCl₃) δppm: 1.44 (9H, s), 1.73-1.80 (1H, m), 2.01-2.18 (1H, m),3.03-3.33 (3H, m), 3.81 (1H, dd, J = 6.1, 10.7 Hz), 5.13-5.22 (1H, m),6.06 (1H, dd, J = 3.4, 9.2 Hz), 7.02 (1H, dd, J = 2.4, 8.4 Hz),7.06-7.12 (1H, m), 7.28 (1H, d, J = 2.4 Hz), 7.50-7.55 (1H, m), 8.06(1H, brs).

TABLE 32

Ref. Ex. No. R1 R2 R4 R4 R5 R6 NMR 242 —H —H —Cl —Cl —H

¹H-NMR (CDCl₃) δppm: 1.43 (9H, s), 1.75-1.84 (1H, m), 2.04-2.18 (1H, m),3.03-3.33 (3H, m), 3.77-3.85 (1H, m), 5.29-5.38 (1H, m), 5.68 (1H, dd, J= 2.1, 12.0 Hz), 6.38-6.46 (1H, m), 7.03 (1H, dd, J = 2.4, 8.5 Hz), 7.29(1H, d, J = 2.3 Hz), 7.54-7.59 (1H, m), 8.10-8.18 (1H, m). 243 —H —H —Cl—Cl —H

¹H-NMR (CDCl₃) δppm: 1.43 (9H, s), 1.72-1.86 (1H, m), 2.04-2.22 (1H, m),3.08-3.33 (3H, m), 3.83 (1H, dd, J = 7.1, 10.8 Hz), 5.28-5.37 (1H, m),6.04 (1H, d, J = 8.6 Hz), 6.63-6.68 (1H, m), 7.03 (1H, dd, J = 2.4, 8.5Hz), 7.27-7.35 (2H, m), 7.51-7.56 (1H, m), 8.17- 8.22 (1H, m). 244 —H —H—F —Cl —H

¹H-NMR (CDCl₃) δppm: 1.44 (9H, s), 1.73-1.90 (1H, m), 2.05-2.22 (1H, m),3.08-3.34 (3H, m), 3.82 (1H, dd, J = 7.2, 10.7 Hz), 5.16-5.25 (1H, m),7.08-7.14 (1H, m), 7.27-7.33 (2H, m), 7.49 (1H, s), 7.89 (1H, brs), 8.09(1H, brs). 245 —H —H —Cl —Cl —H

¹H-NMR (CDCl₃) δppm: 1.44 (9H, s), 1.76-1.89 (1H, m), 2.05-2.28 (1H, m),3.10-3.35 (3H, m), 3.77-3.87 (1H, m), 5.14-5.25 (1H, m), 7.08 (1H, dd, J= 2.4, 8.5 Hz), 7.34 (1H, d, J = 2.3 Hz), 7.52 (1H, s), 7.59 (1H, dd, J= 4.0, 8.2 Hz), 8.10 (1H, brs), 8.66 (1H, brs). 246 —H —H —Cl —Cl —H

¹H-NMR (CDCl₃) δppm: 1.44 (9H, s), 1.75-1.86 (1H, m), 2.09-2.28 (1H, m),3.12-3.34 (3H, m), 3.80 (1H, dd, 7.1, 10.0 Hz), 5.13-5.24 (1H, m), 7.07(1H, dd, J = 2.4, 8.5 Hz), 7.32-7.34 (2H, m), 7.59 (1H, d, J = 8.0 Hz),8.49 (1H, s). 247 —H —H —Cl —Cl —H

¹H-NMR (CDCl₃) δppm: 1.43 (9H, s), 1.82-1.95 (1H, m), 2.09-2.25 (1H, m),3.13-3.37 (3H, m), 3.70-3.80 (1H, m), 4.41-4.50 (1H, m), 6.86 (1H, dd, J= 2.5, 8.6 Hz), 7.13 (1H, d, J = 2.5 Hz), 7.48 (1H, d, J = 8.8 Hz), 8.22(2H, s), 8.82 (1H, s). 248 —H —H —Cl —Cl —H

¹H-NMR (CDCl₃) δppm: 1.44 (9H, s), 1.74-1.88 (1H, m), 2.05-2.20 (1H, m),3.10-3.38 (3H, m), 3.77-3.87 (1H, m), 5.22-5.34 (1H, m), 6.63 (1H, brs),7.02 (1H, dd, J = 2.4, 8.5 Hz), 7.28 (1H, d, J = 2.4 Hz), 7.51 (1H, dd,J = 4.3, 8.4 Hz), 8.32 (2H, brs). 249 —H —H —Cl —Cl —H

¹H-NMR (CDCl₃) δppm: 1.43 (9H, s), 1.79-1.90 (1H, m), 2.04-2.27 (1H, m),3.14-3.36 (3H, m), 3.67-3.80 (1H, m), 4.36-4.45 (1H, m), 6.89 (1H, dd, J= 2.5, 8.5 Hz), 7.16 (1H, d, J = 2.3 Hz), 7.51 (1H, d, J = 8.4 Hz), 8.05(1H, brs). 250 —H —H —F —Cl —H

¹H-NMR (CDCl₃) δppm: 1.43 (9H, s), 1.80-1.98 (1H, m), 2.11-2.28 (1H, m),3.15-3.39 (3H, m), 3.68-3.78 (1H, m), 4.36-4.45 (1H, m), 6.99-7.05 (1H,m), 7.18- 7.27 (2H, m), 7.97 (2H, s).

TABLE 33

Ref. Ex. No. R1 R2 R3 R4 R5 R6 NMR 251 —H —H —F —F —H

¹H-NMR (CDCl₃) δppm: 1.43 (9H, s), 1.79-1.97 (1H, m), 2.01-2.22 (1H, m),3.08-3.38 (3H, m), 3.60-3.78 (1H, m), 4.25-4.41 (1H, m), 6.42-6.62 (2H,m), 6.66 (1H, dd, J = 1.5, 5.0 Hz), 6.78 (1H, dd, J = 1.5, 3.0 Hz),6.91-7.07 (1H, m), 7.30 (1H, d, J = 3.0 Hz) 252 —H —H —Cl —CH₃ —H

¹H-NMR (CDCl₃) δppm: 1.43 (9H, s), 1.78-1.97 (1H, m), 2.03-2.20 (1H, m),2.29 (3H, s), 3.18-3.38 (3H, m), 3.61- 3.82 (1H, m), 4.34-4.43 (1H, m),6.54-6.73 (4H, m), 7.11-7.30 (2H, m). 253 —H —Cl —H —Cl —H

¹H-NMR (CDCl₃) δppm: 1.44 (9H, s), 1.78-1.94 (1H, m), 2.04-2.20 (1H, m),3.13-3.34 (3H, m), 3.67-3.80 (1H, m), 4.29-4.45 (1H, m), 6.48 (2H, d, J= 1.7 Hz), 6.72-6.83 (2H, m), 7.04 (1H, dd, J = 3.1, 1.7 Hz), 7.37-7.42(1H, m). 254 —H —H —F —H —H

¹H-NMR (CDCl₃) δppm: 1.43 (9H, s), 1.82-2.00 (1H, m), 2.01-2.23 (1H, m),3.10-3.40 (3H, m), 3.61-3.79 (1H, m), 4.26-4.42 (1H, m), 6.41-6.44 (1H,m), 6.50 (1H, dd, J = 1.5, 5.0 Hz), 6.89-7.02 (4H, m), 7.18 (1h, brs)255 —H —H —Cl —Cl —H

¹H-NMR (CDCl₃) δppm: 1.43 (9H, s), 1.81-1.98 (1H, m), 2.05-2.24 (1H, m),3.12-3.38 (3H, m), 3.63-3.82 (1H, m), 4.30-4.46 (1H, m), 6.50 (1H, dd, J= 3.0, 9.0 Hz), 6.72- 6.76 (2H, m), 6.96 (1H, dd, J = 1.5, 3.0 Hz), 7.20(1H, brd, J = 9.5 Hz), 7.36 (1H, brs) 256 —H —H —F —Cl —H

¹H-NMR (CDCl₃) δppm: 1.27-1.52 (11H, m), 1.62- 1.82 (3H, m), 1.90-2.05(1H, m), 2.95-3.69 (7H, m), 3.85-4.05 (3H, m), 6.95-7.00 (1H, m),7.00-7.16 (2H, m). 257 —H —H —F —Cl —H

¹H-NMR (CDCl₃) δppm: 1.15-1.35 (2H, m), 1.46 (9H, s), 1.52-1.73 (3H, m),1.76-2.05 (2H, m), 2.91 (2H, d, J = 6.7 Hz), 3.08-3.35 (4H, m),3.35-3.65 (2H, m), 3.80-4.00 (3H, m), 6.76-6.88 (1H, m), 6.95-7.10 (2H,m). 258 —H —H —F —Cl —H

¹H-NMR (CDCl₃) δppm: 1.42 (9H, s), 1.8-1.95 (1H, m), 2.1-2.25 (1H, m),3.15-3.35 (3H, m), 3.65-3.85 (1H, m), 4.45-4.6 (1H, m), 6.7-6.8 (1H, m),6.9-7.0 (2H, m), 7.0- 7.1 (1H, m), 7.21 (1H, s), 7.31 (1H, d, J = 1.7Hz), 7.65- 7.8 (1H, m). 259 —H —H —H —H —H

¹H-NMR (CDCl₃) δppm: 1.42 (9H, s), 1.8-1.95 (1H, m), 2.1-2.25 (1H, m),3.15-3.35 (3H, m), 3.65-3.9 (1H, m), 4.45-4.6 (1H, m), 6.85-7.0 (3H, m),7.05-7.2 (2H, m), 7.25-7.4 (3H, m), 7.6-7.75 (1H, m). 260 —H —H —F —Cl—H

¹H-NMR (CDCl₃) δppm: 1.42 (9H, s), 1.8-2.0 (1H, m), 2.1-2.3 (1H, m),3.15-3.4 (3H, m), 3.65-3.85 (1H, m), 4.4-4.6 (1H, m), 6.65-6.75 (1H, m),6.86 (1H, dd, J = 2.9, 6.3 Hz), 6.95 (1H, dd, J = 2.2, 8.6 Hz), 6.95-7.1(1H, m), 7.35 (1H, s), 7.42 (1H, d, J = 2.1 Hz), 7.74 (1H, d, J = 8.6Hz).

TABLE 34

Ref. Ex. No. R1 R2 R3 R4 R5 R6 NMR 261 —H —H —H —H —H

¹H-NMR (CDCl₃) δppm: 1.41 (9H, s), 1.8-2.0 (1H, m), 2.05-2.3 (1H, m),3.15-3.4 (3H, m), 3.7-3.9 (1H, m), 4.5-4.7 (1H, m), 6.8-6.9 (2H, m),6.9-7.1 (2H, m), 7.2-7.35 (3H, m), 7.42 (1H, d, J = 2.1 Hz), 7.65-7.75(1H, m). 262 —H —H —F —H —H

¹H-NMR (CDCl₃) δppm: 1.42 (9H, s), 1.8-2.0 (1H, m), 2.05-2.3 (1H, m),3.15-3.4 (3H, m), 3.7-3.85 (1H, m), 4.45-4.6 (1H, m), 6.80 (1H, dd, J =2.3, 8.8 Hz), 6.9-7.1 (4H, m), 7.2-7.35 (2H, m), 7.62 (1H, d, J = 8.6Hz). 263 —H —H —F —H —H

¹H-NMR (CDCl₃) δppm: 1.43 (9H, s), 1.8-1.95 (1H, m), 2.05-2.25 (1H, m),3.1-3.4 (3H, m), 3.65-3.9 (1H, m), 4.4-4.6 (1H, m), 6.82 (1H, dd, J =2.0, 8.8 Hz), 6.95-7.2 (6H, m), 7.55-7.7 (1H, m). 264 —H —H —H —H —H

¹H-NMR (CDCl₃) δppm: 1.41 (9H, s), 1.8-1.95 (1H, m), 2.05-2.25 (1H, m),2.42 (3H, d, J = 0.6 Hz), 3.15-3.35 (3H, m), 3.7-3.9 (1H, m), 4.45-4.65(1H, m), 6.75-6.85 (2H, m), 6.9-7.05 (3H, m), 7.15-7.3 (2H, m), 7.45(1H, d, J = 1.9 Hz), 7.63 (1H, dd, J = 3.9, 8.5 Hz). 265 —H —H —H —H —H

¹H-NMR (CDCl₃) δppm: 1.40 (9H, d, J = 2.9 Hz), 1.8-1.95 (1H, m),2.05-2.25 (1H, m), 2.39 (3H, d, J = 0.8 Hz), 3.15-3.35 (3H, m), 3.7-3.9(1H, m), 4.45-4.65 (1H, m), 6.65-6.75 (2H, m), 6.8-6.9 (1H, m), 7.01(1H, dd, J = 1.8, 8.5 Hz), 7.11 (1H, bs),, 7.15-7.3 (2H, m), 7.39 (1H,d, J = 1.9 Hz), 7.81 (1H, dd, J = 3.6, 8.4 Hz). 266 —H —H —H —H —H

¹H-NMR (CDCl₃) δppm: 1.42 (9H, s), 1.8-1.95 (1H, m), 2.05-2.25 (1H, m),3.15-3.35 (3H, m), 3.7-3.9 (1H, m), 4.45-4.6 (1H, m), 6.87 (1H, d, J =1.9 Hz), 6.93 (2H, dd, J = 1.0, 8.5 Hz), 7.05-7.15 (1H, m), 7.23 (1H,s), 7.25-7.4 (4H, m). 267 —H —H —H —H —H

¹H-NMR (CDCl₃) δppm: 1.41 (9H, s), 1.75-1.95 (1H, m), 2.0-2.2 (1H, m),2.57 (3H, s), 3.15-3.35 (3H, m), 3.7-3.9 (1H, m), 4.45-4.6 (1H, m), 6.75(2H, d, J = 7.8 Hz), 6.8-7.0 (3H, m), 7.15-7.3 (2H, m), 7.39 (1H, d, J =1.7 Hz), 7.58 (1H, dd, J = 3.8, 8.2 Hz). 268 —H —H —F —H —H

¹H-NMR (CDCl₃) δppm: 1.42 (9H, s), 1.75-1.95 (1H, m), 2.0-2.2 (1H, m),2.55 (3H, d, J = 1.0 Hz), 3.15-3.35 (3H, m), 3.657-3.85 (1H, m),4.35-4.55 (1H, m), 6.75-6.9 (4H, m), 6.9-7.05 (2H, m), 7.26 (1H, s),7.51 (1H, d, J = 8.6 Hz).

TABLE 35

Ref. Ex. No. R1 R2 R3 R4 R5 R6 NMR 269 —H —H —F —Cl —H

¹H-NMR (CDCl₃) δppm: 1.44 (9H, s), 1.8-1.95 (1H, m), 2.1-2.3 (1H, m),3.15-3.4 (3H, m), 3.7- 3.9 (1H, m), 4.45-4.6 (1H, m), 6.71 (1H, dd, J =2.1, 8.9 Hz), 6.9-7.05 (1H, m), 7.1-7.3 (3H, m), 7.81 (1H, d, J = 6.8Hz), 8.72 ( 1H, s). 270 —H —H —H —H —H

¹H-NMR (CDCl₃) δppm: 1.43 (9H, s), 1.8-2.0 (1H, m), 2.1-2.25 (1H, m),3.15-3.35 (3H, m), 3.75- 3.95 (1H, m), 4.5-4.65 (1H, m), 6.69 (1H, dd, J= 2.2, 8.9 Hz), 7.05-7.15 (3H, m), 7.3-7.4 (1H, m), 7.4-7.5 (2H, m),7.76 (1H, d, J = 7.7 Hz), 8.68 (1H, bs). 271 —H —H —F —H —H

¹H-NMR (CDCl₃) δppm: 1.43 (9H, s), 1.8-1.95 (1H, m), 2.1-2.3 (1H, m),3.1-3.35 (3H, m), 3.7- 3.9 (1H, m), 4.6-4.65 (1H, m), 6.65 (1H, dd, J =2.2, 9.0 Hz), 7.05-7.2 (5H, m), 7.75 (1H, d, J = 8.3 Hz), 8.67 (1H, s).272 —H —H —H —H —H

¹H-NMR (CDCl₃) δppm: 1.43 (9H, s), 1.7-1.9 (1H, m), 2.05-2.25 (1H, m),3.1-3.35 (3H, m), 3.8-3.95 (1H, m), 5.4-5.55 (1H, m), 6.03 (1H, d, J =8.9 Hz), 7.0-7.05 (1H, m), 7.05-7.1 (1H, m), 7.1- 7.2 (2H, m ),7.35-7.55 (3H, m), 7.58 (1H, d, J = 8.9 Hz). 273 —H —H —F —H —H

¹H-NMR (CDCl₃) δppm: 1.43 (9H, s), 1.7-1.9 (1H, m), 2.05-2.25 (1H, m),3.05-3.35 (3H, m), 3.8- 3.95 (1H, m), 5.4-5.55 (1H, m), 6.02 (1H, d, J =8.9 Hz), 7.0-7.2 (6H, m), 7.60 (1H, d, J = 8.8 Hz). 274 —H —H —H —H —H

¹H-NMR (CDCl₃) δppm: 1.43 (9H, s), 1.7-1.9 (1H, m), 2.05-2.25 (1H, m),3.1-3.35 (3H, m), 3.8-3.95 (1H, m), 5.4-5.55 (1H, m), 6.06 (1H, d, J =9.0 Hz), 7.15-7.2 (2H, m), 7.3-7.55 (4H, m), 7.55- 7.65 (1H, m), 7.67(1H, d, J = 10.0 Hz).□ 275 —H —H —F —Cl —H

¹H-NMR (CDCl₃) δppm; 1.43 (9H, s), 1.85-2.00 (1H, m), 2.08-2.26 (1H, m),3.16-3.40 (3H, m), 3.68-3.90 (1H, m), 4.50-4.61 (1H, m), 6.88-6.96 (1H,m), 7.05-7.20 (4H, m), 7.35 (1H, dd, J = 4.2, 8.3 Hz), 7.88-8.05 (2H,m), 8.76 (1H, d, J = 2.9 Hz) 276 —H —H —F —CH₃ —H

¹H-NMR (CDCl₃) δppm: 1.43 (9H, s), 1.75- 1.88 (1H, m), 2.12 (1H, br),2.28 (3H, s), 2.85 (2H, t, J = 6.6 Hz), 3.10 (3H, s), 3.19-3.28 (3H, m),3.48 (2H, t, J = 6.6 Hz), 3.69-3.83 (1H, m), 4.49-4.55 (1H, m), 6.22(1H, d, J = 12.3 Hz), 6.49 (1H, dd, J = 8.1, 8.6 Hz), 6.87-6.95 (2H, m),7.03- 7.09 (1H, m), 7.87 (1H, dd, J = 8.7, 8.7 Hz). 277 —H —H —F —Cl —H

¹H-NMR (CDCl₃) δppm: 1.41 (9H, s), 1.83-1.95 (1H, m), 2.15 (1H, br),3.22-3.34 (3H, m), 3.69- 3.85 (1H, m), 4.06 (3H, s), 4.47 (1H, br),6.65- 6.70 (1H, m), 6.85 (1H, dd, J = 2.8, 6.3 Hz), 6.90 (1H, d, J = 8.8Hz), 6.99-7.05 (1H, m), 7.17 (1H, dd, J = 2.5, 8.9 Hz), 7.26-7.27 (1H,m), 7.77-7.90 (2H, m).

TABLE 36

Ref. Ex. No. R1 R2 R3 R4 R5 R6 NMR 278 —H —H —F —Cl —H

¹H-NMR (CDCl₃) δppm: 1.43 (9H, s), 1.78- 1.90 (1H, m), 2.04-2.17 (1H,m), 2.66 (2H, dd, J = 6.7, 7.7 Hz), 2.86 (2H, dd, J = 6.7, 7.7 Hz),3.19-3.29 (3H, m), 3.36 (3H, s), 3.66-3.78 (1H, m), 4.35-4.41 (1H, m),6.60 (1H, ddd, J = 3.0, 3.8, 9.0 Hz), 6.75-6.78 (2H, m), 6.86 (1H, dd, J= 1.9, 8.6 Hz), 6.93- 7.02 (2H, m). 279 —H —H —F —H —H

¹H-NMR (CDCl₃) δppm: 1.43 (9H, s), 1.78- 1.91 (1H, m), 2.05-2.17 (1H,m), 2.62 (2H, dd, J = 6.1 8.3 Hz), 2.82 (2H, dd, J = 6.1, 8.3 Hz), 3.26(3H, br), 3.33 (3H, s), 3.69- 3.79 (1H, m), 4.41 (1H, br), 6.62 (1H,br), 6.72 (1H, dd, J = 2.5, 8.7 Hz), 6.84-6.91 (3H, m), 7.93-7.03 (2H,m). 280 —H —H —F —Cl —H

¹H-NMR (CDCl₃) δppm: 1.41 (9H, s), 1.81- 1.93 (1H, m), 2.13-2.18 (1H,m), 3.24-3.31 (3H, m), 3.67-3.81 (1H, m), 3.72 (3H, s), 4.41-4.45 (1H,m), 6.62-6.67 (1H, m), 6.73 (1H, d, J = 9.4 Hz), 6.81 (1H, dd, J = 2.7,6.2 Hz), 6.82-7.05 (1H, m), 7.14-7.18 (2H, m), 7.27-7.32 (1H, m), 7.59(1H, d, J = 9.4 Hz). 281 —H —H —CH₃ —F —H

¹H-NMR (CDCl₃) δppm: 1.43 (9H, s), 1.78- 1.91 (1H, m), 2.08-2.18 (1H,m), 2.18 (3H, s), 2.66 (2H, dd, J = 6.6, 7.6 Hz), 2.86 (2H, dd, J = 6.6,7.6 Hz), 3.18-3.27 (3H, m), 3.36 (3H, s), 3.68-3.78 (1H, m), 4.38-4.44(1H, m), 6.36-6.43 (2H, m), 6.79 (1H, d, J = 2.2 Hz), 6.87-7.02 (3H, m).282 —H —H —CH₃ —F —H

¹H-NMR (CDCl₃) δppm: 1.41 (9H, s), 1.60- 1.72 (1H, m), 2.15 (1H, br),2.20 (3H, s), 3.24-3.32 (3H, m), 3.72 (3H, s), 3.75-3.81 (1H, m), 4.46(1H, br), 6.40-6.45 (2H, m), 6.72 (1H, d, J = 9.5 Hz), 7.02 (1H, br),7.18- 7.21 (2H, m), 7.31-7.34 (1H, m), 7.58 (1H, dd, J = 2.9, 9.4 Hz).283 —H —H —F —CH₃ —H

¹H-NMR (CDCl₃) δppm: 1.43 (9H, s), 1.78- 1.90 (1H, m), 2.02-2.13 (1H,m), 2.24 (3H, s), 2.62 (2H, dd, J = 5.4, 8.0 Hz), 2.79-2.84 (2H, m),3.19-3.29 (3H, m), 3.32 (3H, s), 3.98-3.79 (1H, m), 4.35-4.46 (1H, m),6.58 (1H, br), 6.70-6.76 (3H, m), 6.84-6.99 (2H, m). 284 —H —H —F —CH₃—H

¹H-NMR (CDCl₃) δppm: 1.42 (9H, s), 1.80- 1.92 (1H, m), 2.08-2.18 (1H,m), 2.24 (3H, s), 3.24-3.31 (3H, m), 3.69 (3H, s), 3.75-3.81 (1H, m),4.44 (1H, br), 6.69 (1H, d, J = 9.4 Hz), 6.74-6.79 (2H, m), 6.96-7.01(3H, m), 7.21-6.79 (1H, m), 7.55 (1H, d, J = 9.4 Hz).

TABLE 37

Ref. Ex. No. R1 R2 R3 R4 R5 R6 NMR 285 —H —H —F —Cl —H

¹H-NMR (CDCl₃) δppm: 1.42 (9H, s), 1.77-1.82 (1H, m), 2.06-2.10 (1H, m),2.72-2.80 (2H, m), 2.86-2.91 (2H, m), 3.15-3.27 (3H, m), 3.64- 3.73 (1H,m), 3.78 (3H, s), 4.34 (1H, br), 5.09 (2H, br), 6.53-6.89 (7H, m),6.97-7.00 (1H, m), 7.14-7.17 (2H, m). 286 —H —H —F —H —H

¹H-NMR (CDCl₃) δppm: 1.42 (9H, s), 1.61-1.73 (1H, m), 1.90-2.00 (1H, m),2.74 (2H, dd, J = 5.8, 7.9 Hz), 2.87 (2H, dd, J = 5.8, 7.9 Hz), 3.10-3.23 (3H, m), 3.56-3.68 (1H, m), 3.77 (3H, s), 4.23-4.28 (1H, m), 4.81(1H, d, J = 15.5 Hz), 5.02 (1H, d, J = 15.5 Hz), 6.12 (1H, d, J = 2.3Hz), 6.37 (1H, d, J = 8.4 Hz), 6.72-6.99 (9H, m). 287 —H —H —CH₃ —F —H

¹H-NMR (CDCl₃) δppm: 1.42 (9H s), 1.76-1.86 (1H, m), 2.04-2.11 (1H, m),2.18 (3H, s), 2.75-2.79 (2H, m), 2.88- 2.93 (2H, m), 3.13-3.25 (3H, m),3.66-3.76 (1H, m), 3.78 (3H, s), 4.34- 4.38 (1H, m), 5.09 (2H, s), 6.36(2H, m), 6.70-6.74 (2H, m), 6.83-6.91 (3H, m), 6.99 (1H, br), 7.17 (1H,d, J = 8.6 Hz). 288 —H —H —F —CH₃ —H

¹H-NMR (CDCl₃) δppm: 1.42 (9H, s), 1.76-1.85 (1H, m), 2.01-2.09 (1H, m),2.22 (3H, s), 2.71-2.75 (2H, m), 2.84-2.88 (2H, m), 3.13-3.28 (3H, m),3.63-3.75 (1H, m), 3.77 (3H, s), 4.33-4.37 (1H, m), 5.06 (2H, s), 6.47-6.53 (2H, m), 6.69-6.85 (5H, m), 6.91-6.95 (1H, m), 7.14 (2H, d, J = 8.5Hz).

TABLE 38

Ref. Ex. No. R1 R6 NMR 289

¹H-NMR (CDCl₃) δppm: 1.41 (9H, s), 1.8-2.0 (1H, m), 2.1- 2.3 (1H, m),3.15-3.4 (3H, m), 3.7-3.9 (1H, m), 4.45-4.6 (1H, m), 7.0-7.1 (2H, m),7.1-7.2 (1H, m), 7.28 (1H, s), 7.45 (1H, d, J = 1.6 Hz), 7.75-7.8 (1H,m), 8.1-8.3 (2H, m). 290

¹H-NMR (CDCl₃) δppm: 1.42 (9H, s), 1.8-2.0 (1H, m), 2.1- 2.3 (1H, m),3.15-3.4 (3H, m), 3.7-3.9 (1H, m), 4.5-4.7 (1H, m), 6.78 (1H, dd, J =2.0, 8.9 Hz), 7.28 (1H, s), 7.3-7.4 (2H, m), 7.86 (1H, d, J = 9.4 Hz),8.37 (1H, s), 8.45-8.55 (1H, m), 8.75 (1H, s). 291

¹H-NMR (CDCl₃) δppm: 1.40 (9H, s), 1.8-2.0 (1H, m), 2.1- 2.3 (1H, m),3.15-3.4 (3H, m), 3.7-3.9 (1H, m), 4.5-4.65 (1H, m), 6.95-7.2 (3H, m),7.38 (1H, s), 7.53 (1H, d, J = 2.0 Hz), 7.75-7.9 (1H, m), 8.05-8.2 (2H,m). 292

¹H-NMR (CDCl₃) δppm: 1.40 (9H, s), 1.8-2.0 (1H, m), 2.1- 2.3 (1H, m),3.1-3.4 (3H, m), 3.7-3.9 (1H, m), 4.45-4.6 (1H, m), 6.45-6.6 (1H, m),7.09 (1H, dd, J = 1.9, 8.4 Hz), 7.38 (1H, d, J = 5.4 Hz), 7.54 (1H, d, J= 5.4 Hz), 7.65 (1H, d, J = 1.7 Hz), 7.8-7.95 (3H, m). 293

¹H-NMR (CDCl₃) δppm: 1.42 (9H, s), 1.8-2.0 (1H, m), 2.1- 2.3 (1H, m),3.1-3.4 (3H, m), 3.7-3.9 (1H, m), 4.45-4.6 (1H, m), 6.45-6.6 (1H, m),7.07 (1H, dd, J = 2.0, 8.4 Hz), 7.3-7.4 (1H, m), 7.55 (1H, d, J = 5.4Hz), 7.59 (1H, d, J = 2.0 Hz), 7.8-7.9 (2H, m), 7.96 (1H, d, J = 5.4Hz). 294

¹H-NMR (CDCl₃) δppm: 1.40 (9H, s), 1.8-2.0 (1H, m), 2.1- 2.3 (1H, m),3.1-3.4 (3H, m), 3.7-3.9 (1H, m), 4.45-4.6 (1H, m), 6.5-6.65 (1H, m),7.18 (1H, dd, J = 1.9, 8.5 Hz), 7.40 (1H, s), 7.59 (1H, d, J = 1.7 Hz),7.8-8.0 (3H, m).

Example 1 Synthesis of (3,4-dichlorophenyl)phenylpyrrolidin-3-ylaminedihydrochloride

An acetic acid solution (15 ml) containing 3-oxopyrrolidine-1-carboxylicacid tert-butyl ester (0.67 g) and (3,4-dichlorophenyl)phenylamine (0.94g) was stirred at room temperature over night. To the mixture was added1.5 g of sodium triacetoxyborohydride, followed by stirring at roomtemperature for 8 hours. Dichloromethane was added to the reactionsolution and washed with water, followed by drying over magnesiumsulfate. The solvent was distilled off under reduced pressure, and theresidue was then purified by silica gel column chromatography(n-hexane:ethyl acetate=20:1). The solvent was distilled off from thepurified product under reduced pressure, and the residue was dissolvedin 1 N hydrochloric acid-ethanol and heated under reflux for one hour.The reaction solution was concentrated to dryness to thereby obtain 50mg of brown amorphous solid(3,4-dichlorophenyl)phenylpyrrolidin-3-ylamine dihydrochloride.

¹H-NMR (DMSO-d₆) δ ppm:

1.50-1.68 (1H, m), 2.10-2.29 (1H, m), 2.74-2.90 (1H, m), 3.02-3.22 (2H,m), 3.51-3.66 (1H, m), 4.61-4.79 (1H, m), 6.58 (1H, dd, J=2.9 Hz, J=9.0Hz), 6.87 (1H, d, J=2.9 Hz), 7.13-7.19 (2H, m), 7.29-7.44 (2H, m),7.45-7.54 (2H, m), 9.03 (2H, brs).

Example 2 Synthesis of(S)-(3,4-dichlorophenyl)phenylpyrrolidin-3-ylamine dihydrochloride

3(S)-[(3,4-dichlorophenyl)phenylamino]pyrrolidine-1-carboxylic acidtert-butyl ester (0.13 g) was dissolved in 1 N hydrochloric acid-ethanoland heated under reflux for one hour. The reaction solution wasconcentrated to dryness to thereby obtain 0.11 g of brown amorphoussolid 3(S)-(3,4-dichlorophenyl)phenylpyrrolidin-3-ylamine hydrochloride.

¹H-NMR (DMSO-d₆) δ ppm:

1.50-1.68 (1H, m), 2.10-2.29 (1H, m), 2.75-2.90 (1H, m), 3.02-3.23 (2H,m), 3.51-3.65 (1H, m), 4.60-4.80 (1H, m), 6.58 (1H, dd, J=2.9 Hz, J=9.0Hz), 6.87 (1H, d, J=2.9 Hz), 7.12-7.19 (2H, m), 7.29-7.44 (2H, m),7.45-7.54 (2H, m), 9.05 (2H, brs).

Example 3 Synthesis of(3-fluorophenyl)-(S)-pyrrolidin-3-yl-(4-trifluoroamethylphenyl)aminedifumarate

To a 1,2-dichloromethane solution (1 ml) containing((S)-1-benzylpyrrolidin-3-yl)-(3-fluorophenyl)-(4-trifluoromethylphenyl)amine(0.48 g, 1.1 mmol) was added 1-chloroethyl chloroformate (0.82 g, 5.8mmol). The mixture was stirred at room temperature for 15 hours andheated under reflux for 3 hours. The solvent was distilled off underreduced pressure, and 5 ml methanol was then added to the residue andheated under reflux for 3 hours. After distilling the solvent off underreduced pressure, the residue was then dissolved in dichloromethane andwashed with an aqueous saturated sodium hydrogencarbonate solution.After drying over magnesium sulfate, the solvent was distilled off underreduced pressure. The residue was dissolved in ethanol, fumaric acid(128 mg, 1.1 mol) was then added thereto, giving a uniform solution. Thesolvent was distilled off under reduced pressure, and the crystalsproduced by adding dichloromethane to the residue were separated byfiltration and dried, giving 0.24 g of light brown powdery(3-fluorophenyl)-(S)-pyrrolidin-3-yl-(4-trifluoromethylphenyl)aminedifumarate.

Melting point 144.0-146.2° C.

Example 4 Synthesis of(3-chloro-4-fluorophenyl)-(4-methanesulfonylphenyl)-(S)-pyrrolidin-3-ylaminehydrochloride

3(S)-[(3-chloro-4-fluorophenyl)-(4-methanesulfonylphenyl)amino]pyrrolidine-1-carboxylicacid tert-butyl ester (0.42 g, 0.9 mmol) was added to 4 N hydrochloricacid/ethyl acetate, followed by stirring at room temperature for onehour. The reaction solution was concentrated to dryness under reducedpressure to thereby obtain 0.35 g of white powdery(3-chloro-4-fluorophenyl)-(4-methanesulfonylphenyl)-(S)-pyrrolidin-3-ylaminehydrochloride.

¹H-NMR (DMSO-d₆) δ ppm:

1.56-1.68 (1H, m), 2.19-2.29 (1H, m), 2.82-2.94 (1H, m), 3.08 (3H, s),3.10-3.20 (2H, m), 3.57-3.68 (1H, m), 4.70-4.85 (1H, m), 6.69-6.75 (2H,m), 7.32-7.37 (1H, m), 7.58-7.64 (1H, m), 7.65-7.69 (3H, m), 9.10-9.45(2H, m).

Example 5 Synthesis of(3-chloro-4-fluorophenyl)-[4-(pyridin-2-yloxy)butyl]-(S)-pyrrolidin-3-ylaminedifumarate

To a toluene solution (4 ml) containing3(S)-[4-(pyridin-2-yloxy)butylamino]pyrrolidine-1-carboxylic acidtert-butyl ester (0.2 g, 0.6 mmol) and 4-bromo-2-chloro-1-fluorobenzene(0.8 ml, 0.65 mmol) were added tri-tert-butylphosphine.tetrafluoroborate(14 mg, 0.05 mmol), tris(dibenzylideneacetone)dipalladium (11 mg, 0.012mmol) and sodium tert-butoxide (110 mg, 1.2 mol) and heated under refluxunder a nitrogen atmosphere for 12 hours. After cooling to roomtemperature, water was added to the reaction solution, and extractionwith ethyl acetate was conducted. The extract was dried over magnesiumsulfate and concentrated under reduced pressure, and the residue wasthen purified by silica gel column chromatography (n-hexane:ethylacetate=3:1). The solvent was distilled off from the purified productunder reduced pressure. The residue was dissolved in 0.4 mldichloromethane, and trifluoroacetic acid (0.06 ml, 0.8 mmol) was addedthereto, followed by stirring at room temperature for 3 hours. Afterconcentrating under reduced pressure, the residue was purified by HPLC.After collecting objective fractions, the solvent was distilled offunder reduced pressure, and 10% aqueous potassium carbonate solution wasadded to the residue, followed by extraction with dichloromethane. Theextract was dried over magnesium sulfate and concentrated under reducedpressure, and an ethanol solution containing fumaric acid (8.1 mg) wasadded to the residue (ethanol solution) to thereby obtain a uniformsolution. After concentration under reduced pressure, water (3 ml) wasadded to the residue, followed by freeze-drying to thereby obtain 19 mgof white solid(3-chloro-4-fluorophenyl)-[4-(pyridin-2-yloxy)butyl]-(S)-pyrrolidin-3-ylaminedifumarate.

¹H-NMR (DMSO-d₆) δ ppm:

1.45-1.55 (2H, m), 1.65-1.8 (2H, m), 1.8-1.95 (1H, m), 2.05-2.15 (1H,m), 2.6-4.05 (11H, m), 4.25 (2H, t, J=6.5 Hz), 4.3-4.4 (1H, m), 6.55(4H, s), 6.77 (1H, d, J=8.5 Hz), 6.8-6.9 (1H, m), 6.9-7.0 (1H, m), 7.03(1H, dd, J=3 Hz, J=6.5 Hz), 7.22 (1H, dd, J=9 Hz, J=9 Hz), 7.65-7.7 (1H,m), 8.1-8.15 (1H, m).

Example 6 Synthesis of(3-chloro-4-fluorophenyl)-(3-methylsulfanylpropyl)-(S)-pyrrolidin-3-ylaminehydrochloride

An acetic acid solution (3 ml) containing3(S)-[(3-chloro-4-fluorophenyl)amino]pyrrolidine-1-carboxylic acidtert-butyl ester (0.60 g, 1.9 mmol) and 3-methylthiopropionic aldehyde(0.6 g, 5.7 mmol) was stirred at room temperature over night. Sodiumtriacetoxy borohydride (0.81 g, 3.8 mmol) was added to the mixture,followed by stirring at room temperature for 15 hours. Dichloromethanewas added to the reaction solution, and the reaction solution was washedwith water and an aqueous saturated sodium hydrogencarbonate solution,and dried over magnesium sulfate. The solvent was distilled off underreduced pressure, and the residue was then dissolved in 1 N hydrochloricacid-ethanol (10 ml) and heated under reflux for one hour. The reactionsolution was concentrated to dryness to thereby obtain 0.16 g of yellowamorphous solid (3-chloro-4-fluorophenyl)-(3-methylsulfanylpropyl)-(S)-pyrrolidin-3-ylamine hydrochloride.

¹H-NMR (DMSO-d₆) δ ppm:

1.52-1.70 (2H, m), 1.80-2.18 (including 5H, m[2.07 ppm(s)]), 2.40-2.51(2H, m), 2.84-3.49 (6H, m), 4.29-4.49 (1H, m), 6.85-6.95 (1H, m),7.05-7.35 (2H, m), 9.30-9.79 (2H, m).

Example 7 Synthesis of (3-chloro-4-fluorophenyl)pyridin-3-yl-(S)-pyrrolidin-3-ylamine dimethanesulfonate

To a dichlormethane solution (100 ml) containing3(S)-[(3-chloro-4-fluorophenyl)pyridin-3-ylamino]pyrrolidine-1-carboxylicacid tert-butyl ester (16.0 g, 41 mmol) was added trifluoroacetic acid(20 ml), followed by stirring at room temperature for 3 hours. Thesolvent was distilled off under reduced pressure, and an aqueoussaturated sodium hydrogencarbonate solution was added to the residue tomake the residue alkaline, followed by extraction with dichloromethane.The extract was dried over magnesium sulfate, the solvent was distilledoff under reduced pressure, and the residue was purified by basic silicagel column chromatography (dichloromethane:methanol=10:1). The solventwas distilled off from the purified product under reduced pressure. Toan ethanol solution containing the residue was added methanesulfonicacid (9.2 g), and the solvent was then distilled off under reducedpressure. The residue was recrystalized from ethanol to thereby obtain16.9 g of white powdery (3-chloro-4-fluorophenyl)pyridin-3-yl-(S)-pyrrolidin-3-ylamine dimethanesulfonate. Melting point194.0-195.0° C.

The compounds of Example 8 to 1180 shown in the below Tables can beprepared in the same manners as in the above Examples, usingcorresponding starting compounds. In the following Tables, compoundswith the physical properties, such as crystalline form, m.p. (meltingpoint), salt, ¹H-NMR and MS (mass spectrum), were produced actually.

TABLE 39

Ex. No. R1 R2 R3 R4 R5 M.p. (° C.) Salt  8 —H —H —Cl —H —H 173.7-175.0Fumarate  9 —Cl —Cl —H —H —H 160.3-162.6 Fumarate 10 —H —Cl —H —H —H144.2-146.7 Fumarate

TABLE 40

Ex. No. R1 R2 R3 R4 R5 NMR Salt 11 —H —H —Cl —Cl —H 1H-NMR (DMSO-d6) δppm 2 Hydro 1.50-1.68 (1H, m), 2.10-2.29 (1H, m), 2.74-2.90 (1H, m),chloride 3.02-3.22 (2H, m), 3.51-3.66 (1H, m), 4.61-4.79 (1H, m), 6.58(1H, dd, J = 2.9 Hz and 9.0 Hz), 6.87 (1H, d, J = 2.9 Hz), 7.13-7.19(2H, m), 7.29-7.44 (2H, m), 7.45-7.54 (2H, m), 12 —H —H —Cl —Cl —H1H-NMR (DMSO-d6) δ ppm Fumarate 1.49-1.68 (1H, m), 2.05-2.25 (1H, m),2.69-2.82 (1H, m), 2.92-3.15 (2H, m), 3.44-3.60 (1H, m), 4.55-4.74 (1H,m), 6.44 (2H, s), 6.57 (1H, dd, J = 2.9 Hz and 9.0 Hz), 6.85 (1H, d, J =2.8 Hz), 7.11-7.21 (2H, m), 7.29-7.41 (2H, m), 7.43- 7.54 (2H, m)

TABLE 41

Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 M.p. (° C.) Salt 13 —H —H —F —H—H —H —H —F —H —H 155.4-156.4 Fumarate 14 —H —H —F —H —H —H —H —Cl —Cl—H 175.7-180.1 Fumarate 15 —H —H —H —H —F —H —H —Cl —Cl —H 156.6-158.7Fumarate 16 —H —F —H —H —H —H —Cl —Cl —H —H 156.4-158.5 Fumarate

TABLE 42

Ex. No. R1 R2 R3 R4 R5 M.p. (° C.) Salt 17 —H —H —Cl —H —H 152.0-153.0Fumarate 18 —H —Cl —Cl —H —H 144.0-147.9 Fumarate 19 —H —H —SCH₃ —H —H152.9-155.5 Fumarate 20 —H —H —F —H —H 143.0-145.0 Fumarate 21 —Cl —H —H—H —H 138.1-141.8 Fumarate 22 —H —H —CH₃ —H —H 141.7-143.8 Fumarate 23—Cl —Cl —H —H —H 130.2-132.2 Fumarate 24 —H —H —OCF₃ —H —H 131.2-133.6Fumarate 28 —H —Cl —H —H —H 146.6-149.1 Fumarate 26 —H —H —CF₃ —H —H120.3-124.6 Fumarate 27 —H —H —OCH₃ —H —H 137.5-139.2 Fumarate 28 —H —H—NO₂ —H —H 153.0-135.5 Fumarate 29 —H —OCH₃ —H —H —H 135.3-140.7Fumarate 30 —H —H —CO₂CH₃ —H —H 147.5-149.0 Fumarate 31 —H —Cl —H —Cl —H164.8-166.8 Fumarate 32 —H —H —Br —H —H 156-158 Fumarate 33 —H —H—SO₂CH₃ —H —H 184.5-185.8 (dec.) Fumarate 34 —H —F —F —H —H 137.5-138.5Fumarate 35 —H —H —CN —H —H 146.7-149.6 Fumarate 36 —H —Cl —OCH₃ —H —H142-144 Fumarate 37 —H —H —H —F —H 144.2-145.2 Fumarate 38 —H —F —Cl —H—H 155.4-158.4 Fumarate 39 —H —Cl —OC₂H₅ —H —H 135.0-137.2 Fumarate 40—H —Cl —OC₃H₇ —H —H 129.6-132.4 Fumarate

TABLE 43

Ex. No. R1 R2 R3 R4 R5 NMR Salt 41 —H —Cl —Cl —H —H 1H-NMR (DMSO-d6) δppm Hydrochloride 1.50-1.68 (1H, m), 2.10-2.29 (1H, m), 2.75-2.90 (1H,m), 3.02-3.23 (2H, m), 3.51-3.65 (1H, m), 4.60-4.80 (1H, m), 6.58 (1H,dd, J =2.9 Hz and 9.0 Hz), 6.87 (1H, d, J =2.9 Hz), 7.12-7.19 (2H, m),7.20-7.44 (2H, m), 7.45-7.54 (2H, m), 9.05 (2H, brs) 42 —H —H —NH₂ —H —H1H-NMR (DMSO-d6) δ ppm 2 Hydro 1.52-1.69 (1H, m), 2.09-2.24 (1H, m),2.71-2.86 chloride (1H, m), 3.00-3.21 (2H, m), 3.48-3.62 (1H, m),4.52-4.75 (1H, m), 6.82-6.90 (2H, m), 6.98-7.08 (2H, m), 7.14-7.23 (1H,m), 7.24-7.32 (2H, m), 7.35-7.44 (2H, m), 9.30-10.9 (5H, m) 43 —H —H—N(CH₃)₂ —H —H 1H-NMR (DMSO-d6) δ ppm 2 Hydro 1.50-1.70 (1H, m),2.09-2.27 (1H, m), 2.69-2.87 chloride (1H, m), 2.92-3.24 (8H, m with sat δ3.01), 4.60- 4.77 (1H, m), 6.83 (2H, d, J =8.6 Hz), 6.90-7.20 (3H,m), 7.22-7.70 (4H, m), 9.12-9.60 (2H, m) 44 —H —Cl —F —H —H 1H-NMR(DMSO-d6) δ ppm Fumarate 1.50-1.68 (1H, m), 2.05-2.20 (1H, m), 2.72-2.86(1H, m), 2.96-3.13 (2H, m), 3.43-3.57 (1H, m), 4.52-4.69 (1H, m), 6.45(2H, s), 6.77-6.86 (1H, m), 6.97 (2H, d, J =8.2 Hz), 7.05 (1H, dd, J=2.8 Hz and 6.4 Hz), 7.09-7.17 (1H, m), 7.26-7.41 (3H, m) 45 —H —H —CO₂H—H —H 1H-NMR (DMSO-d6) δ ppm Hydrochloride 1.50-1.70 (1H, m), 2.14-2.30(1H, m), 2.70-2.90 (1H, m), 2.99-3.22 (2H, m), 3.51-3.70 (1H, m),4.69-4.89 (1H, m), 6.54-6.64 (2H, m), 7.19-7.29 (2H, m), 7.38-7.48 (1H,m), 7.49-7.59 (2H, m), 7.68-7.79 (2H, m), 9.34 (2H, brs), 12.32 (1H,brs) 46 —H —CH₃ —F —H —H 1H-NMR (DMSO-d6) δ ppm Fumarate 1.5-1.7 (1H,m), 2.0-2.2 (1H, m), 2.20 (3H, s), 2.7-2.9 (1H, m), 3.0-3.2 (2H, m),3.5-3.6 (1H, m), 4.5-4.7 (1H, m), 6.44 (2H, s), 6.6-6.8 (2H, m), 6.8-6.9(2H, m), 6.9-7.0 (1H, m), 7.0-7.3 (3H, m) 47 —H —F —F —OCH₃ —H 1H-NMR(DMSO-d6) δ ppm Fumarate 1.5-1.7 (1H, m), 2.0-2.2 (1H, m), 2.7-2.9 (1H,m), 3.0-3.2 (2H, m), 3.5-3.7 (1H, m), 3.77 (3H, s), 4.6-4.8 (1H, m),6.2-8.4 (2H, m), 6.47 (2H, s), 7.00 (2H, d, J =7.6 Hz), 7.15 (1H, dd, J=7.3 Hz, J =7.3 Hz), 7.3-7.5 (2H, m)

TABLE 44

Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 M.p. (° C.) Salt 48 —H —H —F —H—H —H —H —F —H —H 156.0-157.0 Fumarate 49 —H —H —F —H —H —H —H —Cl —Cl—H 170.5-171.8 Fumarate 50 —H —H —H —H —F —H —H —Cl —Cl —H 133.1-135.8Fumarate 51 —H —H —Cl —H —H —H —F —H —H —H 154.3-155.6 Fumarate 52 —H —H—F —H —H —H —F —H —H —H 143.2-144.4 Fumarate 53 —H —H —CF₃ —H —H —H —F—H —H —H 144.0-146.2 2 Fumarate 54 —H —H —SCH₃ —H —H —H —F —H —H —H161.1-163.2 Fumarate 55 —H —H —F —H —H —H —H —Cl —H —H 174.1-176.2Fumarate 56 —H —H —F —H —H —H —F —F —H —H 148.6-151.3 Fumarate 57 —H —H—F —H —H —H —Cl —F —H —H 176.7-178.4 Fumarate 58 —H —H —F —H —H —H —F—Cl —H —H 163.1-164.1 Fumarate 59 —H —H —H —F —H —H —Cl —F —H —H149.0-152.0 Fumarate 60 —H —CH₃ —H —H —H —H —H —F —H —H 142-143 Fumarate61 —H —Cl —F —H —H —H —H —OCH₃ —H —H 133.1-135.1 Fumarate 62 —H —H —CH₃—H —H —H —Cl —F —H —H 144.0-146.0 Fumarate 63 —H —Cl —F —H —H —H —H—OC₂H₅ —H —H 138.0-141.0 Fumarate 64 —H —H —SCH₃ —H —H —H —H —F —Cl —H136.7-139.0 Fumarate 65 —H —H —C₃H₇ —H —H —H —H —F —Cl —H 136.6-138.0Fumarate 66 —H —H —C(CH₃)₃ —H —H —H —H —F —Cl —H 132.0-134.8 Fumarate 67—H —Cl —F —H —H —H —Cl —F —H —H 165-167 Fumarate 68 —H —H —F —Cl —H —H—H —OH —H —H 191.5-194.5 Fumarate 69 —H —H —F —H —H —H —H —CH₃ —H —H145-148 Fumarate

TABLE 45

Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 M.p. (° C.) Salt 70 —H —H —Br —H—H —H —H —F —Cl —H 141-143 Fumarate 71 —H —H —3-THIENYL —H —H —H —Cl —F—H —H 158-160 Fumarate 72 —H —CF₃ —F —H —H —H —H —F —Cl —H 105-108 2Fumarate 73 —H —H —CN —H —H —H —Cl —F —H —H 174-175 Fumarate 74 —H —H—CF₃ —H —H —H —Cl —F —H —H 169-170 Fumarate 75 —H —H —N(CH₃)₂ —H —H —H—Cl —F —H —H 153-154 Fumarate 76 —H —OCH₃ —H —H —H —H —Cl —F —H —H135-137 Fumarate 77 —H —OC₂H₅ —H —H —H —H —Cl —F —H —H 155-156 Fumarate78 —H —H —NO₂ —H —H —H —CH₃ —F —H —H 162-164 Fumarate 79 —H —H —CN —H —H—H —CH₃ —F —H —H 169-170 Fumarate 80 —H —CH₃ —H —H —H —H —CH₃ —F —H —H129-130 Fumarate 81 —H —H —F —H —H —H —SCH₃ —H —H —H 156-158 Fumarate 82—H —NO₂ —H —H —H —H —CH₃ —F —H —H 108-110 Fumarate 83 —H —OCH₃ —H —H —H—H —H —F —CH₃ —H 140-142 Fumarate 84 —H —H —OC₂H₅ —H —H —H —H —F —CH₃ —H112-113 Fumarate 85 —H —F —H —H —H —H —F —H —H —H 149.0-153.0 (dec.)Fumarate 86 —H —SCH₃ —H —H —H —H —Cl —F —H —H 143-144 Fumarate

TABLE 46

Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 M.p. (° C.) Salt 87 —H —H

—H —H —H —H —F —Cl —H 199-203 3 Hydro chloride 88 —H —H

—H —H —H —Cl —F —H —H 108-110 Fumarate 89 —H —H

—H —H —H —H —F —Cl —H 198-201 3 Hydro chloride 90 —H —H

—H —H —H —H —F —Cl —H 115-117

TABLE 47

Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 NMR Salt 91 —H —F —H —H —H —H —Cl—Cl —H —H 1H-NMR (DMSO-d6) δ ppm 1.49- Fumarate 1.69 (1H, m), 2.03-2.22(1H, m), 2.73-2.86 (1H, m), 2.92-3.10 (2H, m), 3.42-3.58 (1H, m),4.54-4.72 (1H, m), 6.73-6.91 (3H, in with dd at δ6.82, J = 2.7 Hz and8.8 Hz, and dt at δ6.88, J = 2.4 Hz and 11.1 Hz), 6.93-7.01 (1H, m),7.14 (1H, d, J = 2.7 Hz), 7.32-7.43 (1H, m), 7.51 (1H, d, J = 8.8 Hz) 92—H —CH₃ —F —H —H —H —CH₃ —F —H —H 1H-NMR (DMSO-d6) δ ppm Fumarate1.5-1.7 (1H, m), 2.0-2.2 (1H, m), 2.17 (6H, s), 2.7-2.9 (1H, m), 3.0-3.2(2H, m), 3.5-3.6 (1H, m), 4.5-4.7 (1H, m), 6.44 (2H, s), 6.7-6.9 (4H,m), 7.05 (2H, dd, J = 9.1 Hz, J = 9.1 Hz) 93 —H —F —H —H —H —H —CH₃ —F—H —H 1H-NMR (DMSO-d6) δ ppm Fumarate 1.5-1.7 (1H, m), 2.0-2.2 (1H, m),2.23 (3H, s), 2.7-2.9 (1H, m), 3.0-3.2 (2H, m), 3.5-3.6 (1H, m), 4.5-4.7(1H, m), 6.3-6.6 (3H, m), 6.44 (2H, s), 7.0-7.2 (3H, m), 7.22 (1H, dd, J= 9.2 Hz, J = 8.9 Hz) 94 —H —CH₃ —H —H —H —H —Cl —F —H —H 1H-NMR(DMSO-d6) δ ppm 1.5- Fumarate 1.7 (1H, m), 2.0-2.2 (1H, m), 2.27 (3H,s), 2.7-2.9 (1H, m), 3.0-3.2 (2H, m), 3.5-3.6 (1H, m), 4.5-4.7 (1H, m),6.45 (2H, s), 6.7-7.1 (5H, m), 7.2-7.4 (2H, m) 95 —H —CH₃ —H —H —H —H —F—H —H —H 1H-NMR (DMSO-d6) δ ppm Fumarate 1.5-1.7 (1H, m), 2.0-2.2 (1H,m), 2.30 (3H, s), 2.7-2.9 (1H, m), 3.0-3.2 (2H, m), 3.5-3.6 (1H, m),4.5-4.7 (1H, m), 6.3-6.6 (3H, m), 6.43 (2H, s), 6.8-7.0 (2H, m), 7.1-7.3(2H, m), 7.33 (1H, dd, J = 7.7 Hz, J = 7.7 Hz) 96 —H —H —F —H —H —H —CH₃—F —H —H 1H-NMR (DMSO-d6) δ ppm Fumarate 1.5-1.7 (1H, m), 2.0-2.2 (1H,m), 2.48 (3H, s), 2.7-2.9 (1H, m), 3.0-3.2 (2H, m), 3.5-3.6 (1H, m),4.5-4.7 (1H, m), 6.43 (2H, s), 6.7-6.9 (4H, m), 7.0-7.2 (3H, m)

TABLE 48

Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 NMR Salt 97 —H —H —CH₃ —H —H —H—F —H —H —H 1H-NMR (DMSO-d6) δ ppm Fumarate 1.5-1.7 (1H, m), 2.0-2.2(1H, m), 2.33 (3H, s), 2.7-2.9 (1H, m), 3.0-3.2 (2H, m), 3.5-3.6 (1H,m), 4.5-4.7 (1H, m), 6.3-6.6 (3H, m), 6.43 (2H, s), 7.05 (2H, d, J = 8.1Hz), 7.1-7.2 (1H, m), 7.28 (2H, d, J = 8.1 Hz) 98 —H —Cl —CH₃ —H —H —H—F —H —H —H 1H-NMR (DMSO-d6) δ ppm Fumarate 1.5-1.7 (1H, m), 2.0-2.2(1H, m), 2.32 (3H, s), 2.7-2.9 (1H, m), 3.0-3.2 (2H, m), 3.5- 3.6 (1H,m), 4.5-4.7 (1H, m), 6.4-6.7 (3H, m), 6.43 (2H, s), 6.98 (1H, d, J = 8.1Hz), 7.16 (1H, s), 7.2-7.3 (1H, m), 7.38 (1H, d, J = 8.1 Hz) 99 —H —Cl—F —H —H —H —H —C₂H₅ —H —H 1H-NMR (DMSO-d6) δ ppm Fumarate 1.18 (3H, t,J = 7.6 Hz), 1.49-1.68 (1H, m), 2.01-2.19 (1H, m), 2.60 (2H, q, J = 7.6Hz), 2.60-2.81 (1H, m), 2.92-3.14 (2H, m), 3.40- 3.55 (1H, m), 4.50-4.69(1H, m), 6.44 (2H, s), 6.63-6.71 (1H, m), 6.89 (1H, dd, J = 2.8 Hz and6.3 Hz), 7.00 (2H, d, J = 8.3 Hz), 7.19-7.29 (2H, m) 100 —H —F —H —H —H—H —CH₃ —Cl —H —H 1H-NMR (DMSO-d6) δ ppm Fumarate 1.5-1.7 (1H, m),2.0-2.2 (1H, m), 2.30 (3H, s), 2.7-2.9 (1H, m), 3.0-3.2 (2H, m), 3.5-3.6 (1H, m), 4.5-4.7 (1H, m), 6.4-6.7 (3H, m), 6.46 (2H, s), 6.93 (1H,d, J = 8.5 Hz), 7.12 (1H, s), 7.2-7.3 (1H, m), 7.43 (1H, d, J = 8.5 Hz)101 —H —F —H —H —H —H —CN —H —H —H 1H-NMR (DMSO-d6) δ ppm Fumarate1.5-1.7 (1H, m), 2.1-2.3 (1H, m), 2.8-3.0 (1H, m), 3.0-3.2 (2H, m),3.5-3.7 (1H, m), 4.6-4.8 (1H, m), 6.48 (2H, s), 6.7-7.0 (3H, m), 7.1-7.2(1H, m), 7.3-7.5 (4H, m) 102 —H —H —F —Cl —H —H —CN —H —H —H 1H-NMR(DMSO-d6) δ ppm Fumarate 1.5-1.7 (1H, m), 2.0-2.2 (1H, m), 2.7-2.9 (1H,m), 3.0-3.2 (2H, m), 3.6-3.8 (1H, m), 4.6-4.8 (1H, m), 6.44 (2H, s),6.93 (1H, d, J = 8.4 Hz), 7.1-7.2 (1H, m), 7.19 (1H, s), 7.27 (1H, d, J= 7.6 Hz), 7.37 (1H, dd, J = 7.6 Hz, J = 8.2 Hz), 7.4-7.6 (2H, m)

TABLE 49

Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 NMR Salt 103 —H —H —CO₂C₂H₅ —H —H—H —Cl —F —H —H 1H-NMR (DMSO-d6) δ ppm Hydrochloride 1.26 (3H, t, J =7.1 Hz), 1.55-1.68 (1H, m), 2.18-2.29 (1H, m), 2.83- 2.92 (1H, m),3.07-3.19 (2H, m), 3.58-3.68 (1H, m), 4.23 (2H, q, J = 7.1 Hz),4.71-4.82 (1H, m), 6.65 (2H, d, J = 9.0 Hz), 7.28- 7.34 (1H, m),7.55-7.64 (2H, m), 7.76 (2H, d, J = 9.0 Hz), 8.90-9.51 (2H, br) 104 —H—H —CO₂H —H —H —H —Cl —F —H —H 1H-NMR (DMSO-d6) δ ppm Hydrochloride1.52-1.70 (1H, m), 2.15-2.21 (1H, m), 2.81-2.92 (1H, m), 3.06-3.18 (2H,m), 3.53-3.67 (1H, m), 4.65- 4.80 (1H, m), 6.64 (1H, d, J = 9.0 Hz),7.25-7.33 (1H, m), 7.52-7.62 (2H, m), 7.75 (2H, d, J = 9.0 Hz),8.50-10.50 (1H, br), 11.00-13.00 (2H, br) 105 —H —H —SO₂CH₃ —H —H —H —Cl—F —H —H 1H-NMR (DMSO-d6) δ ppm Hydrochloride 1.56-1.68 (1H, m),2.19-2.29 (1H, m), 2.82-2.94 (1H, m), 3.08 (3H, s), 3.10-3.20 (2H, m),3.57-3.68 (1H, m), 4.70-4.85 (1H, m), 6.69- 6.75 (2H, m), 7.32-7.37 (1H,m), 7.58-7.64 (1H, m), 7.65-7.69 (3H, m), 9.10-9.45 (2H, m) 106 —H —H—N(CH₃)₂ —H —H —H —CH₃ —F —H —H 1H-NMR (DMSO-d6) δ ppm 2 Hydro 1.52-1.70(1H, m), 2.08-2.25 (1H, chloride m), 2.24 (3H, s), 2.73-2.87 (1H, m),3.03 (6H, s), 3.02-3.19 (2H, m), 3.50-3.67 (1H, m), 4.65-4.76 (1H, m),6.73 (2H, d, J = 9.1 Hz), 7.00- 7.20 (2H, m), 7.25 (1H, t, J = 9.1 Hz),7.56 (2H, d, J = 7.2 Hz), 9.47 (1H, brs), 9.58 (1H, brs).

TABLE 50

Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 NMR 107 —H —Cl —F —H —H —H —H

—H —H 1H-NMR (CDCl3) δ ppm 1.56-1.86 (5H, m), 2.17-2.30 (1H, m), 2.96(1H, dd, J = 7.4, 11.5 Hz), 3.08-3.21 (6H, m), 3.52 (1H, dd, J = 6.8,11.4 Hz), 4.58-4.72 (1H, m), 6.62 (2H, d, J = 9.0 Hz), 7.02-7.09 (1H,m), 7.21-7.30 (2H, m), 7.69 (2H, d, J = 9.0 Hz).

TABLE 51

Ex. No. R1 R2 R3 R4 R5 R6 M.p. (° C.) Salt 108 —H —Cl —F —H —H

126-129 109 —H —H —H —H —H

141-142 Fumarate 110 —H —H —H —H —H

148-160 Fumarate 111 —H —Cl —F —H —H

144-146 (dec.) Fumarate 112 —H —H —F —Cl —H

168-170 Fumarate 113 —H —H —H —H —H

133-135 Fumarate 114 —H —H —F —H —H

131.6-133.3 Fumarate 115 —H —H —F —H —H

133.2-135.6 Fumarate 116 —H —H —H —H —H

158-160 Hydrochloride

TABLE 52

Ex. No. R1 R2 R3 R4 R5 R6 NMR Salt 117 —H —H —F —H —H

1H-NMR (DMSO-d6) δ ppm 1.5-1.7 (1H, m), 2.0-2.2 (1H, m), 2.7-2.9 (1H,m), 3.0-3.2 (2H, m), 3.4-3.5 (1H, m), 4.4-4.6 (1H, m), 6.02 (2H, s),6.43 (2H, s), 6.54 (1H, d, J = 8.2 Hz), 6.69 (1H, s), 6.7- 6.8 (2H, m),6.90 (1H, d, J = 8.2 Hz), 7.0-7.1 (2H, m) Fumarate 118 —H —H —F —Cl —H

1H-NMR (DMSO-d6) δ ppm 1.5-1.7 (1H, m), 2.0-2.2 (1H, m), 2.7-2.9 (1H,m), 3.0-3.2 (2H, m), 3.5-3.6 (1H, m), 4.5-4.7 (1H, m), 6.06 (2H, s),6.44 (2H, s), 6.5-6.7 (2H, m), 6.7-6.8 (2H, m), 6.96 (1H, d, J = 8.2Hz), 7.12 (1H, s), 7.1-7.3 (1H, m) Fumarate 119 —H —H —H —F —H

1H-NMR (DMSO-d6) δ ppm 1.5-1.7 (1H, m), 2.0-2.2 (1H, m), 2.7-2.9 (1H,m), 2.9-3.1 (2H, m), 3.4-3.6 (1H, m), 4.5-4.7 (1H, m), 6.08 (2H, s),6.3-6.5 (3H, m), 6.44 (2H, s), 6.67 (1H, d, J = 8.1 Hz), 6.82 (1H, s),6.99 (1H, d, J = 8.1 Hz), 7.0-7.2 (1H, m) Fumarate 120 —H —H —F —Cl —H

1H-NMR (DMSO-d6) δ ppm 1.5-1.7 (1H, m), 2.0-2.2 (1H, m), 2.7-2.9 (1H,m), 3.0-3.2 (2H, m), 3.4-3.6 (1H, m), 4.24 (4H, s), 4.5-4.7 (1H, m),6.45 (2H, s), 6.5-6.7 (2H, m), 6.70 (1H, s), 6.7-6.8 (1H, m), 6.91 (1H,d, J = 8.5 Hz), 7.20 (1H, dd, J = 9.1 Hz, J = 9.1 Hz) Fumarate 121 —H —H—F —Cl —H

1H-NMR (DMSO-d6) δ ppm 1.5-1.7 (1H, m), 2.1-2.3 (1H, m), 2.7-2.9 (1H,m), 3.0-3.2 (2H, m), 3.5-3.7 (1H, m), 4.6-4.8 (1H, m), 6.45 (2H, s),6.9-7.0 (1H, m), 7.08 (1H, d, J = 8.5 Hz), 7.23 (1H, dd, J = 9.1 Hz, J =9.1 Hz), 7.42 (1H, d, J = 5.4 Hz), 7.66 (1H, s), 7.80 (1H, d, J = 5.4Hz), 8.02 (1H, d, J = 8.5 Hz) Fumarate 122 —H —H —F —Cl —H

1H-NMR (DMSO-d6) δ ppm 1.5-1.7 (1H, m), 2.1-2.3 (1H, m), 2.7-2.9 (1H,m), 3.0-3.2 (2H, m), 3.5-3.7 (1H, m), 4.6-4.8 (1H, m), 6.46 (2H, s),6.5-6.6 (1H, m), 6.7-6.8 (1H, m), 6.96 (1H, d, J = 2.2 Hz), 7.09 (1H, d,J = 8.7 Hz), 7.18 (1H, dd, J = 9.1 Hz, J = 9.1 Hz), 7.50 (1H, d, J = 2.2Hz), 7.67 (1H, d, J = 8.7 Hz), 8.05 (1H, d, J = 2.2 Hz) Fumarate

TABLE 53

Ex. No. R1 R2 R3 R4 R5 R6 NMR 123 —H —Cl —F —H —H

1H-NMR (CDCl3) δ ppm 1.7-1.9 (2H, m), 2.0-2.25 (1H, m), 2.8-3.0 (3H, m),3.05-3.25 (1H, m), 4.35-4.6 (1H, m), 6.24 (1H, d, J = 1 Hz), 6.4-6.5(1H, m), 6,65-6.75 (1H, m), 6.8-7.0 (2H, m), 7.1-7.2 (1H, m), 7.22 (1H,d, J = 7.5 Hz), 7.36 (1H, d, J = 8 Hz), 8.43 (1H, br). 124 —H —H —H —H—H

1H-NMR (CDCl3) δ ppm 1.68 (1H, br), 1.8-1.95 (1H, m), 2.0-2.2 (1H, m),2.86 (2H, t, J = 7.5 Hz ), 2.99 (1H, dd, J = 5.5, 12 Hz ), 3.13 (1H, dd,J = 6.5, 11.5 Hz), 4.5-4.6 (1H, m), 6.2- 6.3 (1H, m), 6.6-6.75 (3H, m),6.92 (1H, d, J = 7.5 Hz), 7.05-7.25 (4H, m), 7.35 (1H, d, J = 8 Hz),8.34 (1H, br). 125 —H —Cl —F —H —H

1H-NMR (CDCl3) δ ppm 1.65-1.9 (2H, m), 2.0-2.2 (1H, m), 2.8-3.0 (3H, m),3.05-3.2 (1H, m), 4.25-4.4 (1H, m), 6.4-6.5 (1H, m), 6.57 (1H, d, J =3H), 6.67 (1H, dd, J = 3, 6 Hz), 6.75-6.85 (1H, m), 6.90 (1H, dd, J = 9,9 Hz), 7.13 (1H, s), 7.2-7.3 (1H, m), 7.64 (1H, d, J = 8.5 Hz), 8.38(1H, br). 126 —H —Cl —F —H —H

1H-NMR (CDCl3) δ ppm 1.74-1.91 (1H, m), 2.03-2.18 (1H, m), 2.82-3.00(3H, m), 3.14 (1H, dd, J = 6.5 Hz, 11.5 Hz), 4.30-4.40 (1H, m),6.39-6.46 (1H, m), 6.55 (1H, d, J = 3.0 Hz), 6.63 (1H, dd, J = 3.0 Hz,3.0 Hz), 6.83-6.91 (1H, m), 7.18-7.41 (3H, m), 8.50 (1H, br)

TABLE 54

Ex. No. R1 R2 R3 R4 R5 R6 NMR Salt 127 —H —H —H —H —H

1H-NMR (DMSO-d6) δ ppm 1.4-1.6 (1H, m), 2.05-2.25 (1H, m), 2.8-2.95 (1H,m), 3.0-3.2 (2H, m), 3.55-3.7 (1H, m), 4.8-5.0 (1H, m), 6.47 (2H, s),6.53 (2H, d, J = 8 Hz), 6.68 (1H, dd, J = 7.5, 7.5 Hz), 7.0-7.2 (2H, m),7.4-7.7 (4H, m), 7.7-7.85 (1H, m), 8.02 (2H, d, J = 7.5, 7.5 Hz).Fumarate 128 —H —H —F —Cl —H

1H-NMR (DMSO-d6) δ ppm 1.35-1.55 (1H, m), 2.0-2.2 (1H, m), 2.25-5.45(8H, m), 6.3-6.45 (1H, m), 6.48 (2H, s), 6.77 (1H, dd, J = 3, 6 Hz),7.14 (1H, dd, J = 9, 9 Hz), 7.55 (1H, dd, J = 4, 8.5 Hz), 7.62 (1H, dd,J = 1, 7.5 Hz), 7.88 (1H, dd, J = 7.5, 7.5 Hz), 8.12 (1H, d, J = 8.5Hz), 8.22 (1H, d, J = 8 Hz), 8.96 (1H, dd, J = 1.5, 4 Hz). Fumarate 129—H —H —H —H —H

1H-NMR (DMSO-d6) δ ppm 1.45-1.8 (1H, m), 1.95-2.25 (1H, m), 2.6-4.8 (8H,m), 6.44 (2H, s), 6.67 (2H, d, J = 8 Hz), 6.77 (1H, dd, J = 7.5, 7.5Hz), 6.96 (1H, dd, J = 1, 2 Hz), 7.06 (1H, dd, J = 2, 8.5 Hz), 7.16 (2H,dd, J = 7.5, 8.5 Hz), 7.47 (1H, d, J = 2 Hz), 7.65 (1H, d, J = 8.5 Hz),8.04 (1H, d, J = 2 Hz). Fumarate

TABLE 55

Ex. No. R1 R2 R3 R4 R5 R6 M.p. (° C.) Salt 130 —H —Cl —F —H —H

183-186 Hydrochloride 131 —H —Cl —F —H —H

128.0-129.9 Fumarate 132 —H —H —F —H —H

172-176 2 Hydrochloride 133 —H —Cl —F —H —H

183-186 2 Hydrochloride 134 —H —Cl —Cl —H —H

209-211 2Methanesulfonate 135 —H —Cl —Cl —H —H

193-195 2Methanesulfonate 136 —H —Cl —Cl —H —H

122-126 2 Hydrochloride 137 —H —Cl —F —H —H

137.0-140.0 Fumarate 138 —H —H —F —H —H

115-119 (dec.) Fumarate 139 —H —Cl —F —H —H

162.0-164.0 Fumarate

TABLE 56

Ex. No. R1 R2 R3 R4 R5 R6 NMR Salt 140 —H —CH₃ —F —H —H

H-NMR (DMSO-d6) δppm 1.8-2.0 (1H, m), 2.2-2.4 (1H, m), 2.27 (3H, s),3.1-3.3 (3H, m), 3.5-3.7 (1H, m), 4.8-5.0 (1H, m), 6.79 (1H, d. J = 3.7Hz), 7.23 (1H, d, J = 3.7 Hz), 7.3-7.4 (1H, m), 7.43 (1H, d, J = 7.5Hz), 9.25 (1H, brs), 9.44 (1H, brs) 2 Hydro- chloride 141 —H —Cl —F —H—H

1H-NMR (DMSO-d6) δppm 1.79-1.98 (1H, m), 2.14-2.33 (1H, m), 2.19 (3H, d,J = 1.0 HZ), 2.98-3.39 (2H, m), 3.46-3.63 (1H, m), 4.71-4.90 (1H, m),6.93 (1H, d, J = 1.0 Hz), 7.50-7.65 (2H, m), 7.84 (1H, dd, J = 2.5 Hz,6.5 Hz), 9.05 (1H, br), 9.24 (1H, br). 2 Hydro- chloride 142 —H —Cl —F—H —H

1H-NMR (DMSO-d6) δppm 1.55-1.72 (1H, m), 2.05-2.29 (1H, m), 2.82-2.95(1H, m), 3.02-3.14 (2H, m), 3.51-3.65 (1H, m), 4.65-4.83 (1H; m), 6.51(4H, s), 7.20-7.29 (1H, m), 7.46-7.60 (2H, m with dd, J = 2.6 Hz and 6.7Hz), 8.24 (2H, s), 8.68 (1H, s), 2 Fuma- rate 143 —H —Cl —F —H —H

H-NMR (DMSO-d6) δppm 1.6-1.7 (1H, m), 2.1-2.2 (1H, m), 2.57 (3H, s),2.9-3.1 (1H, m), 3.1-3.2 (2H, m), 3.6-3.8 (1H, m), 5.2-5.4 (1H, m), 5.87(1H, d, J = 6.1 Hz), 7.4-7.5 (1H, m), 7.65 (1H, dd, J = 8.9 Hz, J = 8.9Hz), 7.8-7.9 (1H, m), 8.01 (1H, d, J = 6.1 Hz), 9.39 (1H, brs), 9.59(1H, brs) 2 Hydro- chloride 144 —H —Cl —F —H —H

1H-NMR (DMSO-d6) δppm 1.66-1.88 (1H, m), 2.10-2.29 (1H, m), 2.96-3.30(3H, m), 3.48- 3.64 (1H, m), 4.95-5.09 (1H, m), 7.38-7.49 (1H, m), 7.53(1H, d, J = 1.5 Hz), 7.55-7.66 (1H, m), 7.7 (1H, dd, J = 2.5 Hz and 6.8Hz), 7.94 (1H, d, J = 2.7 Hz), 8.19-8.26 (1H, m), 9.30 (1H, brs), 9.62(1H, brs) 2 Hydro- chloride

TABLE 57

Ex. No. R1 R2 R3 R4 R5 R6 NMR Salt 145 —H —Cl —F —H —H

H-NMR (DMSO-d6) δppm 1.8-2.0 (1H, m), 2.2-2.4 (1H, m), 3.1-3.4 (3H, m),3.5-3.7 (1H, m), 5.0-5.2 (1H, m), 7.11 (1H, dd, J = 7.3 Hz, J = 7.7 Hz),7.32 (1H, dd, J = 7.3 Hz, J = 8.2 Hz), 7.6-7.8 (4H, m), 7.8-8.1 (1H, m),9.22 (1H, brs), 9.46 (1H, brs) 2 Hydro- chloride 145 —H —Cl —F —H —H

H-NMR (DMSO-d6) δppm 1.8-2.0 (1H, m), 2.2-2.4 (1H, m), 2.57 (3H, s),3.1- 3.4 (3H, m), 3.5-3.7 (1H, m), 3.72 (3H, s), 4.9-5.1 (1H, m), 6.92(1H, d, J = 8.8 Hz), 7.31 (1H, s), 7.52 (1H, d, J = 8.8 Hz), 7.6-7.7(2H, m), 7.9-8.1 (1H, m), 9.17 (1H, brs), 9.42 (1H, brs) 2 Hydro-chloride 147 —H —H —H —H —H

H-NMR (DMSO-d6) δppm 1.8-2.0 (1H, m), 2.2-2.4 (1H, m), 3.1-3.4 (3H, m),3.6-3.7 (1H, m), 5.0-5.2 (1H, m), 7.08 (1H, dd, J = 7.2 Hz, J = 7.9 Hz),7.31 (1H, dd, J = 7.2 Hz, J = 8.2 Hz), 7.5-7.8 (7H, m), 9.28 (1H, brs),9.50 (1H, brs) 2 Hydro- chloride 148 —H —Cl —F —H —H

H-NMR (DMSO-d6) δppm 1.6-1.8 (1H, m), 2.3-2.4 (1H, m), 2.9-3.1 (1H, m),3.1- 3.2 (2H, m), 3.7-3.8 (1H, m), 5.1-5.2 (1H, m), 7.39 (1H, d, J = 7.2Hz), 7.55 (1H, d, J = 5.7 Hz), 7.7-7.8 (2H, m), 8.08 (1H, d, J = 7.2Hz), 8.22 (1H, d, J = 5.7 Hz), 8.69 (1H, d, J = 7.0 Hz), 9.43 (1H, brs),9.59 (1H, brs) 2 Hydro- chloride

TABLE 58

Ex. No. R1 R2 R3 R4 R5 R6 NMR Salt 149 —H —Cl —F —H —H

1H-NMR (DMSO-d6) δppm 1.6-1.8 (1H, m), 2.2-2.4 (1H, m), 2.9-3.1 (1H, m),3.1-3.3 (2H, m), 3.6-3.8 (1H, m), 4.8-5.0 (1H, m), 7.3-7.4 (1H, m), 7.56(1H, dd, J = 9.0 Hz, J = 9.0 Hz), 7.6-7.7 (1H, m), 7.7- 7.9 (2H, m),8.06 (1H, d, J = 7.8 Hz), 8.22 (1H, d, J = 8.4 Hz), 8.27 (1H, s), 8.67(1H, s), 9.57 (1H, brs), 9.64 (1H, brs) 2 Hydro- chloride 150 —H —Cl —F—H —H

H-NMR (DMSO-d6) δppm 1.82 (3H, s), 1.9-2.1 (1H, m), 2.2-2.3 (1H, m),3.1-3.2 (1H, m), 3.2-3.3 (1H, m), 3.4-3.5 (1H, m), 3.6-3.8 (1H, m),4.9-5.0 (1H, m), 7.0-7.1 (1H, m), 7.3-7.4 (2H, m), 7.4-7.5 (1H, m), 7.68(1H, dd, J = 8.0 Hz, J = 8.3 Hz), 7.81 (1H, d, J = 7.2 Hz), 7.92 (1H, d,J = 8.3 Hz), 8.04 (1H, s), 8.94 (1H, brs), 9.11 (1H, brs) 2 Hydro-chloride 151 —H —CH₃ —F —H —H

H-NMR (CDCl3) δppm 1.8-2.0 (1H, m), 2.32 (3H, s), 2.4-2.5 (1H, m),3.1-3.3 (1H, m), 3.4-3.5 (1H, m), 3.5-3.7 (1H, m), 4.1-4.3 (1H, m),5.2-5.4 (1H, m), 7.0-7.3 (3H, m), 7.5-7.7 (2H, m), 7.89 (1H, d, J = 7.9Hz), 8.04 (1H, s), 8.47 (1H, d, J = 8.3 Hz), 8.87 (1H, s), 9.72 (1H,brs), 10.28 (1H, brs) 2 Hydro- chloride 152 —H —Cl —F —H —H

1H-NMR (DMSO-d6) δppm 1.6-1.8 (1H, m), 2.2-2.4 (1H, m), 2.9-3.1 (1H, m),3.1-3.3 (2H, m), 3.6-3.8 (1H, m), 4.8-5.0 (1H, m), 6.3-6.4 (1H, m), 6.48(2H, s), 6.7-6.8 (1H, m), 7.15 (1H, dd, J = 9.0 Hz, J = 9.0 Hz), 7.6-7.8(3H, m), 8.1-8.3 (1H, m), 8.51 (1H, s), 9.41 (1H, s) Fumarate

TABLE 59

Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 M.p. (° C.) Salt 153 —H —H —H —H —H—H —H —H —H 208.0-211.0 (dec.) 2 Hydrochloride 154 —H —Cl —F —H —H —H —H—H —H 152.4-154.4 Fumarate 155 —H —Cl —F —H —H —H —CH₃ —H —H 141.8-143.1Fumarate 156 —H —Cl —F —H —H —H —H —CH₃ —H 138.6-140.2 Fumarate 157 —H—Cl —F —H —H —H —H —H —H 207.0-208.0 2Methanesulfonate 158 —H —Cl —F —H—H —H -3-THIENYL —H —H 148-151 2 Hydrochloride 159 —H —Cl —F —H —H —H-4-PYRIDYL —H —H 157-158 3 Hydrochloride 160 —H —Cl —F —H —H —H —C₆H₅ —H—H 150-153 2 Hydrochloride 161 —H —Cl —F —H —H —H —H —H —F 83-85 2Hydrochloride 162 —H —Cl —F —H —H —H —H —F —H 150-153 2 Hydrochloride163 —H —Cl —F —H —H —H —CF₃ —H —H 87-89 Hydrochloride 164 —H —Cl —F —H—H —H —H —OCH₃ —H 153-156 2 Hydrochloride 165 —H —Cl —F —H —H —Br —H —H—H 220-223 Hydrochloride 166 —H —Cl —F —H —H —Cl —H —H —H 219-220Hydrochloride 167 —H —Cl —F —H —H —H —C₂H₅ —H —H 112-115 Fumarate 168 —H—Cl —F —H —H -2-THIENYL —H —H —H  98-103 Hydrochloride 169 —H —Cl —F —H—H -3-THIENYL —H —H —H 95-98 Hydrochloride 170 —H —Cl —F —H —H —H —H —Cl—H 125-128 2 Hydrochloride 171 —H —Cl —Cl —H —H —H —F —H —H 111-115 2Hydrochloride 172 —H —Cl —Cl —H —H —H —Br —H —H 115-118 2 Hydrochloride173 —H —Cl —Cl —H —H —H —H —H —F 75-80 2 Hydrochloride 174 —H —Cl —Cl —H—H —H —H —F —H 125-128 2 Hydrochloride

TABLE 60

Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 M.p. (° C.) Salt 175 —H —Cl —Cl —H —H—H —H —OCH₃ —H 160-165 2 Hydrochloride 176 —H —Cl —F —H —H —H —CN —H —H211-213 Hydrochloride 177 —H —Cl —Cl —H —H —H —CN —H —H 126-130 2Hydrochloride 178 —H —Cl —Cl —H —H —H —H —CH₃ —H 204-207 2 Hydrochloride179 —H —Cl —Cl —H —H —H —CF₃ —H —H 100-105 2 Hydrochloride 180 —H —Cl—Cl —H —H —OCH₃ —H —H —H 190-195 2 Hydrochloride 181 —H —Cl —Cl —H —H —H—H —CN —H 135-138 2 Hydrochloride 182 —H —Cl —F —H —H —H —Cl —H —H163-165 Fumarate 183 —H —Cl —F —H —H —H —Cl —H —H 190-191 2Hydrochloride 184 —H —H —F —H —H —H —Cl —H —H 95-97 Fumarate 185 —H —CH3—F —H —H —H —Cl —H —H 156-157 Fumarate 186 —H —Cl —F —H —H —H —Br —H —H159-160 Fumarate 187 —H —H —F —H —H —H —H —H —H 226-228 2 Hydrochloride188 —H —H —Cl —Cl —H —H —H —H —H 135-138 2 Hydrochloride 189 —H —H —Cl—Cl —H —H —Cl —H —H 123-125 2 Hydrochloride 190 —H —H —F —Cl —H —H-3-FURYL —H —H 157-160 2 Hydrochloride 191 —H —H —F —Cl —H —H -2-THIENYL—H —H 152-155 2 Hydrochloride 192 —H —H —F —Cl —H —H —F —H —H 115-120 2Hydrochloride

TABLE 61

Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 M.p. (° C.) Salt 193 —H —Cl —F —H —H—H

—H —H 143-145 2 Hydrochloride 194 —H —Cl —F —H —H —H

—H —H 145-146 2 Hydrochloride 195 —H —Cl —F —H —H —H

—H —H 113-116 2 Hydrochloride 196 —H —Cl —F —H —H —H

—H —H 128-130 2 Hydrochloride 197 —H —Cl —F —H —H —H

—H —H 116-120 2 Hydrochloride 198 —H —H —F —H —H —H

—H —H 132-135 2 Hydrochloride 199 —H —Cl —F —H —H —H

—H —H 142-145 3 Hydrochloride 200 —H —Cl —F —H —H —H

—H —H 212-215 4 Hydrochloride 201 —H —Cl —F —H —H —H

—H —H 208-211 4 Hydrochloride 202 —H —Cl —F —H —H —H

—H —H 200-203 3 Hydrochloride

TABLE 62

Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 M.p. (° C.) Salt 203 —H —Cl —F —H —H—H

—H —H 160-162 4 Hydrochloride 204 —H —Cl —F —H —H —H

—H —H 167-170 2 Hydrochloride 205 —H —Cl —F —H —H —H

—H —H 200-203 3 Hydrochloride 206 —H —Cl —F —H —H —H

—H —H 243-246 3 Hydrochloride 207 —H —Cl —F —H —H —H

—H —H 145-147 4 Hydrochloride 208 —H —H —F —Cl —H —H

—H —H 143-145 3 Hydrochloride 209 —H —H —F —H —H —H

—H —H 131-133 3 Hydrochloride 210 —H —H —F —Cl —H —H

—H —H 184-186 3 Hydrochloride 211 —H —H —F —Cl —H —H

—H —H 160-162 3 Hydrochloride 212 —H —H —F —Cl —H —H

—H —H 133-135 2 Hydrochloride

TABLE 63

Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 M.p. (° C.) Salt 213 —H —Cl —F —H —H—H

—H —H 128-131 2 Hydrochloride 214 —H —Cl —F —H —H —H

—H —H 164-166 2 Hydrochloride

TABLE 64

Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 M.p. (° C.) Salt 215 —H —Cl —F —H —H

—H —H —H 181-183 4 Hydrochloride

TABLE 65

Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 NMR Salt 216 —H —Cl —F —H —H —H —H —H—H 1H-NMR (DMSO-d6) δppm 2 Hydro- 1.59-1.82 (1H, m), 2.11-2.35 (1H, m),2.85-3.28 (3H, chloride m), 3.50-3.71 (1H, m), 5.01-5.21 (1H, m),6.25-6.46 (1H, m), 6.82-6.92 (1H, m), 7.33-7.50 (1H, m), 7.55-7.70 (2H,m), 7.74 (1H, dd, J = 2.4 Hz and 6.7 Hz), 8.11-8.21 (1H, m), 9.20-9.75(2H, m) 217 —H —H —H —H —H —CH₃ —H —H —H 1H-NMR (DMSO-d6) δppm Hydro-1.60-1.79 (1H, m), 2.13-2.30 (1H, m), 2.50 (1H, s), 2.86- chloride 3.02(1H, m), 3.05-3.20 (2H, m), 3.59-3.64 (1H, m), 5.29- 5.45 (1H, m),5.80-6.00 (1H, m), 6.68 (1H, d, J = 7.2 Hz), 7.32 (1H, d, J = 7.2 Hz),7.41-7.51 (2H, m), 7.53-7.61 (2H, m), 9.49 (2H, brs) 218 —H —H —H —H —H—H —CH₃ —H —H 1H-NMR (DMSO-d6) δppm 2 Hydro- 1.61-1.79 (1H, m), 2.19(3H, s), 2.23-2.39 (1H, m), 2.85- chloride 3.20 (3H, m), 3.59-3.74 (1H,m), 5.05-5.22 (1H, m), 6.20- 6.40 (1H, m), 7.32-7.41 (2H, m), 7.46-7.62(4H, m), 7.94-7.99 (1H, m), 9.30-9.65 (2H, br) 219 —H —H —H —H —H —H —H—CH₃ —H 1H-NMR (DMSO-d6) δppm 2 Hydro- 1.60-1.80 (1H, m), 2.19 (3H, s),2.24-2.48 (1H, m), 2.81- chloride 3.00 (1H, m), 3.02-3.19 (2H, m),3.58-3.64 (1H, m), 6.30 (1H, d, J = 8.8 Hz), 7.32-7.42 (2H, m),7.49-7.68 (4H, m), 7.93-8.01 (1H, m), 9.50 (2H, brs) 220 —H —Cl —F —H —H—CH₃ —H —H —H 1H-NMR (DMSO-d6) δppm Fumarate 1.52-1.76 (1H, m),1.92-2.18 (1H, m), 2.32 (3H, s), 2.90-3.22 (3H, m), 3.50-3.72 (1H, m),5.05-5.25 (1H, m), 5.72-5.90 (1H, m), 6.35-6.70 (3H, m), 7.11-7.75 (3H,m) 221 —H —CF₃ —F —H —H —H —H —H —H 1H-NMR (DMSO-d6) δppm 2 Hydro-1.65-1.83 (1H, m), 2.16-2.31 (1H, m), 3.00-3.31 (3H, chloride m),3.52-3.67 (1H, m), 5.03-5.16 (1H, m), 6.25 (1H, d, J = 8.5 Hz),6.80-6.85 (1H, m), 7.52-7.59 (1H, m), 7.67-7.81 (1H, m), 7.84 (1H, d, J= 6.5 Hz), 8.19-8.22 (1H, m), 9.07 (1H, br), 9.34 (1H, br).

TABLE 66

Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 NMR Salt 222 —H —Cl —F —Cl —H —H —H—CF₃ —H H-NMR (DMSO-d6) δppm 2 Hydro- 1.7-1.8 (1H, m), 2.1-2.3 (1H, m),3.0-3.2 (2H, m), 3.2-3.3 chloride (1H, m), 3.5-3.7 (1H, m), 5.1-5.2 (1H,m), 6.24 (1H, s), 7.03 (1H, d, J = 5.3 Hz), 7.4-7.5 (1H, m), 7.63 (1H,dd, J = 9.0 Hz, J = 9.0 Hz), 7.7-7.8 (1H, m), 8.47 (1H, d, J = 5.3 Hz),9.21 (1H, brs), 9.53 (1H, brs) 223 —H —Cl —F —H —H —OCH₃ —H —H —H H-NMR(DMSO-d6) δppm 2 Hydro- 1.6-1.7 (1H, m), 2.1-2.2 (1H, m), 2.9-3.1 (1H,m), 3.1- chloride 3.2 (2H, m), 3.6-3.8 (1H, m), 3.85 (3H, s), 5.1-5.2(1H, m), 5.52 (1H, d, J = 8.0 Hz), 6.12 (1H, d, J = 7.8 Hz), 7.3-7.4(2H, m), 7.5-7.7 (2H, m), 9.25 (1H, brs), 9.45 (1H, brs) 224 —H —CH₃ —F—H —H —H —H —H —Cl H-NMR (CDCl3) δppm 2 Hydro- 2.1-2.4 (2H, m), 2.23(3H, s), 3.2-3.3 (1H, m), 3.4-3.6 chloride (2H, m), 3.6-3.8 (1H, m),4.7-4.9 (1H, m), 6.7-7.1 (4H, m), 7.57 (1H, d, J = 7.1 Hz), 8.52 (1H, d,J = 3.9 Hz), 9.53 (1H, brs), 10.10 (1H, brs) 225 —H —CH₃ —F —H —H —H —H—H —H H-NMR (CDCl3) δppm 2 Hydro- 1.8-2.0 (1H, m), 2.35 (3H, s), 2.5-2.7(1H, m), 3.1-3.4 chloride (2H, m), 3.4-3.6 (1H, m), 4.1-4.3 (1H, m),5.3-5.5 (1H, m), 6.47 (1H, d, J = 8.9 Hz), 7.05 (1H, s), 7.2-7.4 (3H,m), 7.78 (1H, dd, J = 8.9 Hz, J = 7.6 Hz), 8.25 (1H, d, J = 4.7 Hz),9.51 (1H, brs), 10.39 (1H, brs) 226 —H —H —F —H —H —H —CH₃ —H —H H-NMR(CDCl3) δppm 2 Hydro- 1.8-2.0 (1H, m), 2.31 (3H, s), 2.35 (3H, s),2.6-2.7 (1H, chloride m), 3.1-3.3 (1H, m), 3.3-3.4 (1H, m), 3.4-3.6 (1H,m), 4.1- 4.3 (1H, m), 5.3-5.5 (1H, m), 6.42 (1H, d, J = 9.3 Hz), 7.1-7.4(3H, m), 7.61 (1H, d, J = 9.3 Hz), 8.04 (1H, s), 9.51 (1H, brs), 10.47(1H, brs) 227 —H —CH₃ —F —H —H —CH₃ —H —H —H H-NMR (CDCl3) δppm 2 Hydro-1.8-2.0 (1H, m), 2.36 (3H, s), 2.4-2.5 (1H, m), 2.92 chloride (3H, s),3.2-3.4 (2H, m), 3.4-3.6 (1H, m), 4.1-4.3 (1H, m), 6.0-6.1 (1H, m), 6.20(1H, d, J = 8.9 Hz), 6.73 (1H, d, J = 7.1 Hz), 7.1-7.3 (3H, m), 7.5-7.7(1H, m), 9.29 (1H, brs), 10.98 (1H, brs)

TABLE 67

Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 NMR Salt 228 —H —CH₃ —F —H —H —OCH₃—H —H —H H-NMR (CDCl3) δppm 2 Hydro- 1.9-2.1 (1H, m), 2.26 (3H, s),2.2-2.4 (1H, m), 3.2-3.5 (3H, chloride m), 3.8-3.9 (1H, m), 3.90 (3H,s), 5.0-5.2 (1H, m), 5.58 (1H, d, J = 8.1 Hz), 6.08 (1H, d, J = 8.0 Hz),6.9-7.1 (3H, m), 7.22 (1H, dd, J = 8.0 Hz, J = 8.1 Hz), 9.74 (1H, brs),10.18 (1H, brs) 229 —H —CH₃ —F —H —H —H —H —CH₃ —H H-NMR (CDCl3) δppm 2Hydro- 1.9-2.0 (1H, m), 2.31 (3H, s), 2.37 (3H, s), 2.6-2.7 (1H,chloride m), 3.1-3.3 (1H, m), 3.3-3.4 (1H, m), 3.4-3.6 (1H, m), 4.1- 4.3(1H, m), 5.4-5.6 (1H, m), 6.18 (1H, s), 6.84 (1H, d, J = 6.3 Hz),7.2-7.4 (3H, m), 8.11 (1H, d, J = 6.3 Hz), 9.55 (1H, brs), 10.64 (1H,brs) 230 —H —CH₃ —F —H —H —H —H —H —CH₃ H-NMR (CDCl3) δppm 2 Hydro- 1.96(3H, s), 2.0-2.1 (1H, m), 2.27 (3H, s), 2.4-2.6 (1H, m), chloride3.4-3.7 (3H, m), 3.8-4.0 (1H, m), 5.3-5.5 (1H, m), 7.0-7.3 (3H, m),7.3-7.5 (1H, m), 7.89 (1H, d, J = 7.0 Hz), 8.50 (1H, d, J = 5.1 Hz),9.77 (1H, brs), 10.39 (1H, brs) 231 —H —Cl —F —H —H —H —Cl —H —Cl 1H-NMR(CDCl3) δppm 1.65-1.81 (1H, m), 1.99-2.09 (1H, m), 2.81-3.11 (4H, m),4.50-4.61 (1H, m), 6.80-6.87 (1H, m), 7.00 (1H, dd, J = 2.8, 6.4 Hz),7.05 (1H, t, d, J = 8.7 Hz), 7.61 (1H, d = 2.3 Hz), 8.26 (1H, d, J = 2.3Hz). 232 —H —Cl —F —H —H —H —CN —H —H 1H-NMR (CDCl3) δppm 1.63-1.77 (1H,m), 2.01-2.15 (1H, m), 2.78-2.96 (3H, m), 3.28-3.35 (1H, m), 5.02-5.16(1H, m), 6.03 (1H, d, J = 9.0 Hz), 7.02-7.10 (1H, m), 7.24-7.32 (2H, m),7.44 (1H, dd, J = 2.3, 9.0 Hz), 8.46 (1H, d, J = 2.3 Hz). 233 —H —Cl —F—H —H —CN —H —H —H 1H-NMR (CDCl3) δppm 1.82-1.95 (1H, m), 2.19-2.25 (1H,m), 3.11-3.29 (3H, m), 3.62-3.70 (1H, m), 5.01-5.11 (1H, m), 6.27 (1H,d, J = 8.8 Hz), 7.06 (1H, d, J = 7.3 Hz), 7.10-7.15 (1H, m), 7.23-7.31(2H, m), 7.39 (1H, dd, J = 7.3, 8.8 Hz).

TABLE 68

Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 NMR Salt 234 —H —Cl —Cl —H —H —H —H—Cl —H 1H-NMR (DMSO-d6) δppm 2 Hydro- 1.68-1.82 (1H, m), 2.11-2.24 (1H,m), 3.01-3.14 (2H, m), chloride 3.15-3.29 (1H, m), 3.48-3.65 (1H, m),4.98-5.10 (1H, m), 6.21 (1H, s), 6.88 (1H, d, J = 5.4 Hz), 7.35-7.40(1H, m), 7.76 (1H, d, J = 1.7 Hz), 7.82 (1H, d, J = 8.4 Hz), 8.21 (1H,d, J = 5.4 Hz), 9.19 (1H, brs), 9.55 (1H, brs). 235 —H —Cl —F —H —H —H—H —H —Cl 1H-NMR (CDCl3) δppm Hydro- 1.74 (1H, brs), 2.30 (1H, brs),3.34 (1H, brs), 3.55 (2H, brs), chloride 3.73 (1H, brs), 4.79 (1H, brs),6.90-7.13 (4H, m), 7.60 (1H, d, J = 7.7 Hz), 8.58 (1H, s), 9.48 (1H,brs), 10.38 (1H, brs). 236 —H —Cl —F —H —H —H -3- —H —H 1H-NMR (DMSO-d6)δppm 2 Hydro- PYRIDYL 1.65-1.90 (1H, m), 2.13-2.31 (1H, m), 2.99-3.28(3H, m), chloride 3.58-3.72 (1H, m), 5.13-5.28 (1H, m), 6.26 (1H, d, J =9.0 Hz), 7.45 (1H, ddd, J = 2.6, 4.3, 8.6 Hz), 7.65 (1H, t, J = 9.0 Hz),7.76 (1H, dd, J = 2.5, 6.7 Hz), 8.02 (1H, dd, J = 2.5, 9.0 Hz), 8.11(1H, dd, J = 5.7, 8.1 Hz), 8.78-8.87 (3H, m), 9.25 (1H, s), 9.60 (1H,brs), 9.85 (1H, brs).

TABLE 69

Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 M.p. (° C.) Salt 237 —H —Cl —F —H —H—H —H —H —H 194.0-195.0 2Methanesulfonate 238 —H —Cl —F —H —H —H —C₆H₅—H —H 158-161 2 Hydrochloride 239 —H —Cl —F —H —H —H —F —H —H 75-80 2Hydrochloride 240 —H —Cl —F —H —H —H —F —H —H 121-123 Fumarate 241 —H—Cl —Cl —H —H —H —CN —H —H 150-155 2 Hydrochloride 242 —H —Cl —Cl —H —H—H —H —H —H 108-110 Hydrochloride 243 —H —H —F —H —H —H —H —H —H 232-2342 Hydrochloride 244 —H —Cl —F —H —H —H —Cl —H —H 136-137 Fumarate 245 —H—Cl —F —H —H —H —H -4-PYRIDYL —H 200-205 3 Hydrochloride

TABLE 70

Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 M.p.(° C.) Salt 246 —H —Cl —F —H —H—H —H

—H 252-257 4 Hydro chloride 247 —H —H —F —Cl —H —H

—H —H 223-225 3 Hydro chloride 248 —H —H —F —Cl —H —H

—H —H 156-157 2 Hydro chloride

TABLE 71

Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 NMR Salt 249 —H —H —H —H —H —H —H —H—H 1H-NMR (DMSO-d6) δ ppm Fumarate 1.50-1.70 (1H, m), 2.10-2.31 (1H, m),2.75-2.90 (1H, m), 3.00-3.22 (2H, m), 3.51-3.68 (1H, m), 4.60-4.80 (1H,m), 6.47 (2H, s), 7.01-7.10 (2H, m), 7.13-7.30 (3H, m), 7.32-7.45 (2H,m), 8.07 (1H, d, J = 2.7 Hz), 8.13 (1H, dd, J = 1.4 Hz and 4.5 Hz) 250—H —Cl —F —H —H —H —H —H —H 1H-NMR (DMSO-d6) δ ppm 2 Hydrochloride1.51-1.74 (1H, m), 2.13-2.35 (1H, m), 2.80-2.99 (1H, m), 3.01-3.20 (2H,m), 3.52-3.72 (1H, m), 4.75-4.94 (1H, m), 7.39-7.48 (1H, m), 7.59-7.69(2H, m), 7.71-7.81 (2H, m), 8.19-8.29 (2H, m) 251 —H —F —H —H —H —H —H—H —H 1H-NMR (DMSO-d6) δ ppm 2 Hydrochloride 1.62-1.81 (1H, m),2.20-2.37 (1H, m), 2.88-3.24 (3H, m), 3.56-3.72 (1H, m), 5.10-5.27 (1H,m), 6.27 (1H, d, J = 8.6 Hz), 6.82-6.92 (1H, m), 7.37 (2H, d, J = 7.1Hz), 7.49-7.72 (4H, m with d at δ 7.58, J = 7.6 Hz), 8.15 (1H, dd, J =1.2 Hz and 5.6 Hz), 9.30-9.80 (2H, m) 252 —H —H —H —H —H —H —F —H —H1H-NMR (DMSO-d6) δ ppm Hydrochloride 1.50-1.71 (1H, m), 2.05-2.28 (1H,m), 2.75-2.92 (1H, m), 3.00-3.24 (2H, m), 3.45-3.62 (1H, m), 4.52-4.78(1H, m), 6.86-6.98 (2H, m), 7.01-7.11 (1H, m), 7.15 (1H, dd, J = 3.4 Hzand 7.2 Hz), 7.28-7.39 (2H, m), 7.48-7.62 (1H, m), 7.84-7.93 (1H, m),9.20-9.80 (2H, m) 253 —H —CH₃ —F —H —H —H —H —H —H 1H-NMR (DMSO-d6) δppm 2 Methanesulfonate 1,5-1.7 (1H, m), 2.0-2.2 (1H, m), 2,27 (3H, s),2.36 (6H, s), 2.8-3.0 (1H, m), 3.0-3.3 (2H, m), 3.6-3.7 (1H, m), 4.7-4.9(1H, m), 7.2-7.4 (3H, m), 7.55 (1H, d, J = 8.9 Hz), 7.75 (1H, d, J = 8.9Hz), 8.14 (1H, s), 8.22 (1H, d, J = 5.1 Hz), 8.83 (2H, brs) 254 —H —Cl—F —H —H —H —OCH₃ —H —H 1H-NMR (DMSO-d6) δ ppm Fumarate 1.5-1.7 (1H, m),2.1-2.2 (1H, m), 2.7-2.9 (1H, m), 3.0-3.2 (2H, m), 3.5-3.6 (1H, m), 3.86(3H, s), 4.6-4.7 (1H, m), 6.46 (2H, s), 6.5-6.7 (1H, m), 6.85 (1H, d, J= 9.1 Hz), 6.90 (1H, d, J = 8.7 Hz), 7.21 (1H, dd, J = 9.1 Hz, J = 9.1Hz), 7.56 (1H, d, J = 8.7 Hz), 8.03 (1H, s)

TABLE 72

Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 NMR Salt 255 —H —F —F —H —H —H —H —H—H H-NMR (DMSO-d6) δ ppm 2 Hydrochloride 1.6-1.8 (1H, m), 2.2-2.3 (1H,m), 2.9-3.0 (1H, m), 3.0-3.2 (2H, m), 3.6-3.8 (1H, m), 4.8-4.9 (1H, m),7.23 (1H, d, J = 8.7 Hz), 7.5-7.8 (4H, m), 8.21 (1H, s), 8.36 (1H, d, J= 5.1 Hz), 9.49 (1H, brs), 9.55 (1H, brs) 256 —H —Cl —Cl —H —H —H —H —H—H H-NMR (DMSO-d6) δ ppm 2 Hydrochloride 1.6-1.8 (1H, m), 2.2-2.3 (1H,m), 2.9-3.0 (1H, m), 3.1-3.2 (2H, m), 3.6-3.8 (1H, m), 4.8-4.9 (1H, m),7.26 (1H, d, J = 8.6 Hz), 7.6-7.8 (4H, m), 8.32 (1H, s), 8.34 (1H, d, J= 4.6 Hz), 9.38 (1H, brs), 9.50 (1H, brs) 257 —H —CF₃ —F —H —H —H —H —H—H 1H-NMR (DMSO-d6) δ ppm 2 Hydrochloride 1.52-1.72 (1H, m), 2.19-2.35(1H, m), 2.84-3.01 (1H, m), 3.05-3.21 (2H, m), 3.59-3.73 (1H, m),4.81-4.94 (1H, m), 7.61 (1H, dd, J = 2.0 Hz, 8.5 Hz), 7.71-7.76 (3H, m),7.82 (1H, d, J = 7.0 Hz), 8.26-8.29 (2H, m), 9.40 (1H, br), 9.50 (1H,br). 258 —H —Cl —H —H —H —H —H —H —H H-NMR (DMSO-d6) δ ppm 2Hydrochloride 1.6-1.8 (1H, m), 2.2-2.3 (1H, m), 2.8-2.9 (1H, m), 3.0-3.2(2H, m), 3.5-3.7 (1H, m), 4.8-5.0 (1H, m), 7.29 (1H, d, J = 7.8 Hz),7.47 (1H, s), 7.5-7.7 (3H, m), 7.76 (1H, d, J = 8.9 Hz), 8.21 (1H, s),8.29 (1H, d, J = 5.3 Hz), 9.5-9.8 (2H, br) 259 —H —Cl —F —H —H —H —H —Br—H H-NMR (DMSO-d6) δ ppm 2 Hydrochloride 1.5-1.7 (1H, m), 2.1-2.3 (1H,m), 2.8-3.0 (1H, m), 3.0-3.2 (2H, m), 3.5-3.7 (1H, m), 4.7-4.9 (1H, m),7.2-7.4 (1H, m), 7.50 (1H, s), 7.56 (1H, dd, J = 9.0 Hz, J = 9.0 Hz),7.6-7.7 (1H, m), 7.97 (1H, s), 8.23(1H, s), 9.41 (1H, brs), 9.51 (1H,brs)

TABLE 73

Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 NMR Salt 260 —H —Cl —F —H —H —H —H—COC₆H₅ —H H-NMR (DMSO-d6) δ ppm 2 Hydrochloride 1.6-1.8 (1H, m),2.2-2.4 (1H, m), 2.9-3.0 (1H, m), 3.1-3.2 (2H, m), 3.5-3.7 (1H, m),4.8-5.0 (1H, m), 7.3-7.4 (1H, m), 7.5-7.9 (8H, m), 8.37 (1H, s), 8.39(1H, s), 9.4-9.7 (2H, br) 261 —H —Cl —F —H —H —H —H —C₆H₅ —H H-NMR(DMSO-d6) δ ppm 2 Hydrochloride 1.6-1.8 (1H, m), 2.2-2.4 (1H, m),2.9-3.0 (1H, m), 3.1-3.2 (2H, m), 3.6-3.8 (1H, m), 4.9-5.1 (1H, m),7.4-7.5 (1H, m), 7.5-7.6 (3H, m), 7.62 (1H, dd, J = 8.9 Hz, J = 8.9 Hz),7.7-7.8 (1H, m), 7.79 (2H, d, J = 8.3 Hz), 7.87 (1H, s), 8.00 (1H, s),8.57 (1H, s), 9.46 (1H, brs), 9.58 (1H, brs) 262 —H —Cl —F —H —H —H —H—SCH₃ —H H-NMR (DMSO-d6) δ ppm 2 Hydrochloride 1.5-1.7 (1H, m), 2.1-2.3(1H, m), 2.55 (3H, s), 2.8-3.0 (1H, m), 3.0-3.2 (2H, m), 3.5-3.7 (1H,m), 4.7-4.9 (1H, m), 7.2-7.3 (1H, m), 7.33 (1H, s), 7.5-7.6 (2H, m),7.81 (1H, s), 8.10 (1H, s), 9.22 (1H, brs), 9.36 (1H, brs) 263 —H —Cl —F—H —H —H —H —SC₆H₅ —H H-NMR (DMSO-d6) δ ppm 2 Hydrochloride 1.5-1.7 (1H,m), 2.1-2.3 (1H, m), 2.8-2.9 (1H, m), 3.0-3.2 (2H, m), 3.5-3.7 (1H, m),4.7-4.9 (1H, m), 6.77 (1H, s), 7.2-7.3 (1H, m), 7.40 (5H, s), 7.4-7.6(2H, m), 8.01 (1H, s), 8.08 (1H, s), 9.38 (1H, brs), 9.46 (1H, brs) 264—H —Cl —F —H —H —H —Cl —Cl —H H-NMR (DMSO-d6) δ ppm 2 Hydrochloride1.5-1.7 (1H, m), 2.1-2.3 (1H, m), 2.8-2.9 (1H, m), 3.0-3.2 (2H, m),3.5-3.7 (1H, m), 4.7-4.9 (1H, m), 7.2-7.4 (1H, m), 7.44 (1H, s), 7.54(1H, dd, J = 9.0 Hz, J = 9.0 Hz), 7.6-7.7 (1H, m), 7.75 (1H, s), 9.36(2H, brs)

TABLE 74

Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 NMR Salt 265 —H —Cl —F —H —H —H —H—C₂H₅ —H H-NMR (DMSO-d6) δ ppm 2 Hydrochloride 1.16 (3H, t, J = 7.0 Hz),1.5-1.7 (1H, m), 2.2-2.3 (1H, m), 2.69 (2H, q, J = 7.0 Hz), 2.8-2.9 (1H,m), 3.0-3.2 (2H, m), 3.5-3.7 (1H, m), 4.8-5.0 (1H, m), 7.2-7.3 (1H, m),7.59 (1H, s), 7.6-7.7 (2H, m), 7.95 (1H, s), 8.19 (1H, s), 9.42 (1H,brs), 9.55 (1H, brs) 266 —H —Cl —F —H —H —H —H —Cl —H H-NMR (DMSO-d6) δppm 2 Hydrochloride 1.5-1.7 (1H, m), 2.1-2.3 (1H, m), 2.8-2.9 (1H, m),3.0-3.2 (2H, m), 3.5-3.7 (1H, m), 4.7-4.9 (1H, m), 7.2-7.3 (1H, m), 7.33(1H, s), 7.55 (1H, dd, J = 9.0 Hz, J = 9.0 Hz), 7.6-7.7 (1H, m), 7.92(1H, s), 8.13 (1H, s), 9.44 (1H, brs), 9.53 (1H, brs) 267 —H —Cl —F —H—H —H —H —CN —H H-NMR (DMSO-d6) δ ppm 2Methanesutfonate 1.5-1.7 (1H, m),2.1-2.3 (1H, m), 2.44 (6H, s), 2.8-3.0 (1H, m), 3.1-3.2 (2H, m), 3.6-3.8(1H, m), 4.7-4.9 (1H, m), 7.2-7.3 (1H, m), 7.5-7.7 (2H, m), 7.67 (1H,s), 8.17 (1H, s), 8.45 (1H, s), 8.79 (1H, brs), 8.84 (1H, brs) 268 —H—Cl —F —H —H —H —CN —H —H 1H-NMR (DMSO-d6) δ ppm 2 Hydrochloride1.60-1.78 (1H, m), 2.18-2.32 (1H, m), 2.83-2.99 (1H, m), 3.05-3.19 (2H,m), 3.55-3.70 (1H, m), 4.75-4.87 (1H, m), 7.05 (1H, dd, J = 3.0, 8.9Hz), 7.32-7.43 (1H, m), 7.64 (1H, t, J = 9.0 Hz), 7.74 (1H, dd, J = 2.5,6.7 Hz), 7.78 (1H, d, J = 8.9 Hz), 8.03 (1H, d, J = 2.9 Hz), 9.25 (1H,brs), 9.38 (1H, brs). 269 —H —Cl —F —H —H —H —CN —H —H 1H-NMR (CDCl3) δppm 1.67-1.81 (1H, m), 2.10-2.25 (1H, m), 2.83-2.89 (1H, m), 2.90-3.00(2H, m), 3.27-3.34 (1H, m), 4.35-4.52 (1H, m), 8.86 (1H, dd, J = 3.0,5.4 Hz), 7.05-7.10 (1H, m), 7.23-7.28 (1H, m), 7.30 (1H, d, J = 8.8Hz),7.44 1H d, J = 8.8 Hz , 8.00 1H, d, J = 3.0 Hz).

TABLE 75

Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 NMR Salt 270 —H —Cl —Cl —H —H —H —CN—H —H 1H-NMR (CDCl3) δ ppm 1.70-1.82 (1H, m), 2.11-2.25 (1H, m),2.83-2.90 (1H, m), 2.94-3.00 (2H, m), 3.26-3.33 (1H, m), 4.35-4.50 (1H,m), 6.90 (1H, dd, J = 3.0, 8.8 Hz), 7.04 (1H, dd, J = 2.4, 8.5 Hz), 7.28(1H, d, J = 2.8 Hz), 7.45 (1H, d, J = 8.8 Hz), 7.59 (1H, d, J = 8.5 Hz),8.03 (1H, d, J = 2.8 Hz). 271 —H —H —Cl —F —H —H —H —H —H H-NMR(DMSO-d6) δ ppm 2Methane 1.6-1.8 (1H, m), 2.2-2.3 (1H, m), 2.36 (6H, s),2.9-3.0 (1H, sulfonate m), 3.1-3.3 (2H, m), 3.6-3.8 (1H, m), 4.8-4.9(1H, m), 7.09 (1H, d, J = 8.5 Hz), 7.4-7.5 (1H, m), 7.7-7.9 (3H, m),8.30 (1H, s), 8.36 (1H, d, J = 6.1 Hz), 8.76 (1H, brs), 8.84 (1H, brs)

TABLE 76

Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 NMR 272 —H —Cl —F —H —H —H —H

—H 1H-NMR (CDCl3) δ ppm 1.67-1.81 (1H, m), 2.08-2.19 (1H, m), 2.87-3.00(3H, m), 3.24-3.31 (1H, m), 4.40-4.48 (1H, m), 6.95-7.05 (1H, m),7.16-7.24 (3H, m), 7.61 (2H, d, J = 8.3 Hz), 7.74 (2H, d, J = 8.3 Hz),8.12 (1H, d, J = 2.6 Hz), 8.43 (1H, d, J = 1.5 Hz).

TABLE 77

Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 M.p. (° C.) Salt 273 —H —Cl —Cl —H —H—H —H —H —H 229-231 2 Hydro chloride

TABLE 78

Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 NMR Salt 274 —H —H —H —H —H —H —H —H—H 1H-NMR (DMSO-d6) δ ppm 1.52-1.71 (1H, m), Hydrochloride 2.21-2.39(1H, m), 2.40-2.99 (1H, m), 3.00-3.25 (2H, m), 3.61-3.78 (1H, m),4.98-5.12 (1H, m), 6.55-7.10 (2H, m), 7.35-7.45 (2H, m), 7.53-7,71 (3H,m), 8.22-8.38 (2H, m), 9.80 (2H, brs), 14.46 (1H, brs) 275 —H —Cl —F —H—H —H —H —H —H 1H-NMR (DMSO-d6) δ ppm 2 Hydro 1.56-1,76 (1H, m),2.20-2.38 (1H, m), 2,89-3.02 chloride (1H, m), 3.03-3.20 (2H, m),3.60-3.75 (1H, m), 4.94-6.11 (1H, m), 6.70-7.15 (2H, m), 7.41-7.53 (1H,m), 7.66-7.76 (1H, m), 7.85 (1H, dd, J = 2.5 Hz and 6.9 Hz), 8.33 (2H,d, J = 7.0 Hz), 9.44-9.80 (2H, m.) 276 —H —Cl —F —H —H —H —CH₃ —H —HH-NMR (DMSO-d6) δ ppm 2 Hydro 1.6-1.8 (1H, m), 2.2-2.4 (1H, m), 2.50(3H, s), chloride 2.8-3.0 (1H, m), 3.1-3.2 (2H, m), 3.6-3.8 (1H, m),4.9-6.1 (1H, m), 6.4-7.0 (2H, m), 7.4-7.5 (1H, m), 7.69 (1H, dd, J = 9.0Hz, J = 9.0 Hz), 7.8-7.9 (1H, m), 8.20 (1H, d, J = 5.5 Hz), 9.54 (1H,brs), 9.70 (1H, brs)

TABLE 79

Ex. No. R1 R2 R3 R4 R5 R6 M.p. (° C.) Salt 277 —H —H —H —H —H

124.7-126.7 Fumarate 278 —H —Cl —F —H —H

135.0-136.0 Fumarate 279 —H —F —H —H —H

139.0-141.0 Fumarate

TABLE 80

Ex. No. R1 R2 R3 R4 R5 R6 NMR Salt 280 —H —H —F —H —H

1H-NMR (DMSO-d6) δ ppm 0.99-1.50 (2H, m), 1.51-2.20 (4H, m), 2.80-3.65(7H, m), 3.60-3.99 (2H, m), 4.10-481 (1H, m), 7,01-7.99 (4H, m),9.15-9.90 (2H, m) Hydrochloride

TABLE 81

Ex. No. R1 R2 R3 R4 R5 R6 NMR Salt 281 —H —Cl —F —H —H

1H-NMR (DMSO-d6) δ ppm 1.68-1.83 (1H, m), 2.05-2.22 (1H, m), 2.75- 3.20(3H, m), 3.41-3.59 (1H, m), 4.51-4.72 (1H, m), 5.80-5.90 (1H, m),6.57-6.65 (1H, m), 2 Hydro chloride 6.69-6.79 (2H, m), 6.80-8.88 (1H,m), 7.09- 7.19 (1H, m), 9,10-9.50 (2H, m), 11.05 (1H, brs) 282 —H —C1 —F—H —H

1H-NMR (DMSO-d6) δ ppm 1.6-1.8 (1H, m), 2.1-2.2 (1H, m), 2,8-3.0 (1H,m), 3.1-3.3 (2H, m), 3.4-3.6 (1H, m), 4.6-4.7 (1H, m), 6.56 (1H, d, J =9.6 Hz), 6.7-6.8 (1H, m), 6.94 (1H, d, J = 9.2 Hz), 7.25 (1H, dd, J =9.2 Hz, J = 9.0 Hz), 7.43 (1H, d, J = 9.6 Hz), 2 Hydro bromide 7.58 (1H,s), 8.90 (2H, brs) 283 —H —Cl —F —H —H

1H-NMR (DMSO-d6) δ ppm 1.6-1.8 (1H, m), 2.1-2.2 (1H, m), 2.8-3.0 (1H,m), 3.0-3.2 (2H, m), 3.4-3.6 (1H, m), 4.5-4.7 (1H, m), 5.04 (1H, d, J =14.5 Hz), 5.12 (1H, d, J =14.5 Hz), 6.48 (2H, s), 6.49 (1H, d, J = 9.5Fumarate Hz), 6.6-6.7 (1H, m), 6.8-6.9 (1H, m), 7.1-7.5 (7H, m), 7.94(1H, s) 284 —H —Cl —F —H —H

1H-NMR (DMSO-d6) δ ppm 1.6-1.8 (1H, m), 2.1-2.2 (1H, m, 2.8-3.0 (1H, m),3.0-3.2 (2H, m), 3.42 (3H, s), 3.4-3.6 (1H, m), 4.5-4.7 (1H, m), 6.46(1H, d, J = 9.5 Hz), 6.6-6.7 (1H, m), 6.8-6.9 (1H, m), 7.22 (1H, dd, 2Hydro chloride J = 9.1 Hz, J = 9.1 Hz), 7.30 (1H, d. J = 9.5 Hz), 7.87(1H, s), 9.42 (1H, brs), 9.49 (1H, brs) 285 —H —C1 —F —H —H

1H-NMR (CDCl3) δ ppm: 1.65-2.0 (2H, m), 2.05-2.25 (1H, m), 2.7-3.05 (3H,m), 3.1-3.3 (1H, m), 4.4-4.55 (1H, m), 6.4-6.55 (1H, m), 6.65-6.75 (1H,m), 6.86 (1H, dd, J = 9, 9 Hz), 7.0-7.1 (2H, m), 7.1-7.45 (4H, m), 8.51(1H, br).

TABLE 82

Ex. No. R2 R6 NMR Salt 286

1H-NMR (DMSO-d6) δ ppm 1.56-1.76 (1H, m), 2.01-2.17 (2H, m), 2.21-2.35(1H, m), 2.76-3.01 (5H, m), 3.05-3.25 (2H, m), 3.59-3.74 (1H, m),4.79-4.91 (1H, m), 7,07 (1H, dd, J = 1.5 Hz, 7.5 Hz), 7.20 (1H, s),7.42-7.53 (2H, m), 7.70-7.76 2 Hydro chloride (1H, m), 8.06 (1H, d, J =3.0 Hz), 8.19 (1H, d, J = 5.0 Hz), 9.46 (1H, br), 9.52 (1H, br). 287

1H-NMR (DMSO-d6) δ ppm 1.62-1.81 (1H, m), 1.99-2.15 (2H, m), 2.20-2.37(1H, m), 2.84-3.21 (7H, m), 3.57-3.73 (1H, m), 5.10-5.26 (1H, m), 6.38(1H, d, J = 8.5 Hz), 6.90 (1H, dd, J = 6.5 Hz, 6.5 Hz), 7.11 (1H, dd, J= 1.5 Hz, 8.0 Hz), 2 Hydro chloride 7.24 (1H, s), 7.44 (1H, d, J = 8.0Hz), 7.68 (1H, dd, J = 7.5 Hz, 7.5 Hz), 8.12 (1H, dd, J = 1.5 Hz, 5.5Hz), 9.42 (1H, br), 9.51 (1H, br). 288

1H-NMR (DMSO-d6) δ ppm 1.64-1.85 (1H, m), 1.99-2.25 (3H, m), 2.85-3.28(7H, m), 3.47-3.63 (1H, m), 5.02-5.15 (1H, m), 7.09 (1H, dd, J = 2.0 Hz,8.0 Hz), 7.22 (1H, s), 7.38-7.43 (2H, m), 7.88 (1H, d, J = 2.5 Hz),8.19-8.21 (1H, m), 9.26 (1H, 2 Hydro chloride br), 9.54 (1H, br). 289

1H-NMR (DMSO-d6) δ ppm 1.66-1.71 (1H, m), 2.15-2.25 (1H, m), 2.82-2.91(1H, m), 3.01-3.14 (2H, m), 3.54-3.62 (1H, m), 4.70-4.85 (1H, m), 6.47(2H, s), 7.09 (1H, dd, J = 1.9 Hz and 8.5 Hz), 7.12-7.16 (1H, m),7.20-7.26 (1H, m), 7.45 Fumarate (1H, d, J = 5.4 Hz), 7.77 (1H, d, J =5.4 Hz), 7.85-7.88 (1H, m), 7.91 (1H, d, J = 8.5 Hz), 8.04-8.09 (2H, m)290

1H-NMR (DMSO-d6) δ ppm: 1.55-1.8 (1H, m), 2.1- 2.35 (1H, m),2.75-4.5(1H, m), 4.65-4.9 (1H, m), 6.46 (2H, s), 7.09 (1H, dd, J = 2.5,9 Hz), 7.2-7.35 (2H, m), 7.35-7.55 (2H, m), 7.60 (1H, d, J = 2 Hz),7.75-7.95 (3H, m), 8.1-8.25 (2H, m). Fumarate 291

1H-NMR (DMSO-d6) δ ppm: 1.45-1.7 (1H, m), 2.1- 2.3 (1H, m), 2.6-4.3 (7H,m), 4.75-4.95 (1H, m), 6.48 (2H, s), 6.85-6.95 (1H, m), 7.1-7.25 (2H,m), 7.25-7.4 (1H, m), 7.51 (1H, dd, J = 7.5, 7.5 Hz), 7.78 (1H, d, J =5.5 Hz), 7.85-8.0 (2H, m), 8.10 (1H, d, J = 8 Hz). Fumarate 292

1H-NMR (DMSO-d6) δ ppm: 1.4-1.7 (1H, m), 2.0- 2.3 (1H, m), 2.6-4.65 (7H,m), 4.85-5.0 (1H, m), 6.49 (2H, s), 6.8-6.9 (1H, m), 7.12 (1H, dd, J =4.5, 8.5), 7.45-7.7 (4H, m), 7.77 (1H, d, J = 8 Hz), 7.84 (1H, d, J = 3Hz), 7.91 (1H, dd, J = 1, 4.5 Hz), 7.99- 8.1 (2H, m). Fumarate

TABLE 83

Ex. No. R2 R6 NMR Salt 293

1H-NMR (DMSO-d6) δ ppm: 1.55-1,75 (1H, m), 2.15-2.3 (1H, m), 2.55-4.55(7H, m), 4.75-4.9 (1H, m), 6.48 (2H, s), 6.95-7.05 (1H, m), 7.1-7.25(1H, m), 7.38 (1H, d, J = 7.5 Hz), 7.45-7.6 (2H, m), 7.75 (1H, d, J =5.5 Hz), 7.85-8.05 (3H, m). Fumarate 294

1H-NMR (DMSO-d6) δ ppm 1.59-1.69 (1H, m), 2.21-2.49 (1H, m), 2.82-3.24(3H, m), 3,61-3.75 (1H, m), 4.84-5.02 (1H, m), 7.90 (1H, d, J = 2.0 Hz),7.92 (1H, d, J = 5.5 Hz), 8.14 (1H, d, J = 2.8 Hz), 8.19 (1H, d, J = 5.5Hz), 8.24 (1H, d, 2 Hydro chloride J = 8.5 Hz) 295

1H-NMR (CDCl3) δ ppm: 1.7-1.9 (2H, m), 2.16 (1H, dt, J = 7.5, 7.5 Hz),2.85-3.0 (3H, m), 3.21 (1H, dd, J = 6.5, 11.5 Hz), 4.45 (1H, tt, J =6.5, 6.5 Hz), 6.77 (1H, dd, J = 1, 2 Hz), 6.8-6.9 (1H, m), 7.0-7.1 (2H,m), 7.38 (1H, d, J = 2 Hz), 7.55 (1H, d, J = 8.5 Hz), 7.68 (1H, d, J = 2Hz), 7.99 (1H, dd, J = 1.5, 4.5 Hz), 8.04 (1H, d, J = 3 Hz). 296

1H-NMR (CDCl3) δ ppm: 1.75-1.95 (1H, m), 2.05- 2.4 (2H, m), 2.88 (2H, t,J = 7.5 Hz), 2.98 (1H, dd, J = 5.5, 11.5 Hz), 3.17 (1H, dd, J = 6.5, 12Hz), 3.83 (3H, s), 4.35-4.5 (1H, m), 6.48 (1H, dd, J = 0.5, 3 Hz),6.75-6.85 (1H, m), 6.9-7.05 (2H, m), 7.11 (1H, d, J = 3 Hz), 7.3-7.45(2H, m), 7.92 (1H, dd, J = 1.5, 4.5 Hz), 8.03(1H, d, J = 3 Hz). 297

1H-NMR (DMSO-d6) δ ppm: 1.3-1.65 (1H, m), 2.0-2.25 (1H, m), 2.6-5.65(8H, m), 6.46 (2H, s), 6.54 (2H, d, J = 8 Hz), 6.71 (1H, dd, J = 7.5,7.5 Hz), 7.12 (2H, dd, J = 7.5, 8.5 Hz), 7.52 (1H, dd, J = 4, 8.5 Hz),7.59 (1H, dd, J = 1, 7.5 Hz), 7.87 (1H, dd, J = 7.5, 8.5 Hz), 8.09 (1H,d, J = 8.5 Hz), 8.15-8,25 (1H, m), 8.93 (1H, dd, J = 1.5, 4 Hz).Fumarate 298

1H-NMR (DMSO-d6) δ ppm: 1.55-1.75 (1H, m), 2.15-2.35(1H, m), 2.6-5.75(8H, m), 6.50 (2H, s), 6.95-7.05 (1H, m), 7.1-7.2 (1H, m), 7.3-7.5 (3H,m), 7.9-8.0 (3H, m), 8.0-8.1 (1H, m). Fumarate 299

1H-NMR (DMSO-d6) δ ppm: 1.65-1.85 (1H, m), 2.15-2.35 (1H, m), 2.85-3.05(1H, m), 3.05-3.3 (2H, m), 3.5-3.7 (1H, m), 4.7-4.9 (1H, m), 6.9- 7.05(2H, m), 7.38 (2H, d, J = 5.5 Hz), 7.55 (2H, d, J = 1.5 Hz), 7.76 (2H,d, J = 5.5 Hz), 7.91 (2H, d, J = Hydro chloride 8.5 Hz), 9.28 (1H, br),9.50 (1H, br). 300

1H-NMR(DMSO-d6) δ ppm: 1.65-1.85 (1H, m), 2.15-2.35 (1H, m), 2.8-3.05(1H, m), 3.05-3.25 (2H, m), 3.35-3.8 (1H, m), 4,75-4.9 (1H, m), 6.9- 7.0(2H, m), 7.39 (2H, d, J = 5.5 Hz), 7.64 (2H, d, J = 5.5 Hz), 7.70 (2H,s), 7.79 (2H, d, J = 8.5 Hz), Hydro chloride 9.24 (1H, br), 9.43 (1H,br).

TABLE 84

Ex. No. R1 R2 R3 R4 R5 R6 M.p. (° C.) Salt 301 —H —Cl —F —H —H-cyclo-C₆H₁₁ 194.9-198.1 (dec.) Hydrochloride 302 —H —Cl —F —H —H—CH₂-cyclo-C₆H₁₁ 158.5-161.0 Hydrochloride

TABLE 85

Ex. No. R1 R2 R3 R4 R5 R6 NMR Salt 303 —H —Cl —F —H —H -cyclo—C₆H₁₁1H-NMR (DMSO-d6) δppm Fumarate 0.80-1.09 (3H, m), 1.15-1.38 (2H, m),1.42-1.58 (2H, m), 1.60-1.87 (5H, m), 1.88-2.05 (1H, m), 2.81-3.12 (3H,m), 3.12-3.29 (1H, m), 4.09-4.25 (1H, m), 7.00-7.10 (1H, m), 7.20 (1H,dd, J = 2.6Hz and 6.7Hz), 7.24-7.34 (1H, m), 304 —H —H —F —H —H-cyclo—C₆H₁₁ 1H-NMR (DMSO-d6) δppm Hydrochloride 0.59-1.55 (8H, m),1.58-2.43 (5H, m), 2.81-4.11 (4H, m), 4.40-5.22 (1H, m), 7.00-8.20 (4H,m), 9.25-10.45 (2H, m) 305 —H —Cl —F —H —H —(CH₂)₃SCH₃ 1H-NMR (DMSO-d6)δppm Hydrochloride 1.52-1.70 (2H, m), 1.80-2.18 (5H, m with s at δ2.07),2.40-2.51 (2H, m), 2.84-3.49 (6H, m), 4.29-4.49 (1H, m), 6.85-6.95 (1H,m), 7.05-7.35 (2H, m), 9.30-9.79 (2H, m) 306 —H —Cl —F —H —H -cyclo—C₅H₉1H-NMR (DMSO-d6) δppm Hydrochloride 1.15-1.88 (9H, m), 1.95-2.18 (1H,m), 2.71-3.49 (4H, m), 3.60-3.85 (1H, m), 4.35-4.55 (1H, m), 7.05-7.55(3H, m), 9.01-9.45 (2H, m) 307 —H —Cl —F —H —H —(CH₂)₃NHCH₃ 1H-NMR(DMSO-d6) δppm 3 Hydro 1.5-3.5 (14H, m), 3.7-3.9 (1H, m), 4.1-4.6chloride (2H, m), 5-5.75 (1H, brs), 6.8-7.1 (1H, m), 7.1- 7.3 (2H, m),8.7-9.7 (2H, m) 308 —H —Cl —F —H —H —(CH₂)₃N(CH₃)₂ 1H-NMR (DMSO-d6) δppm3 Hydro 1.7-2.3 (3H, m), 2.70 (3H, s), 2.72 (3H, s), chloride 2.9-3.4(8H, m), 4.38(1H, m), 6.8-7.0 (1H, m), 7.1-7.2 (1H, m), 7.28 (1H, t, J =9.1Hz), 9.2-9.4 (1H, brs), 9.6-9.8 (1H, brs), 10.3-10.6 (1H, brs)

TABLE 86

Ex. No. R1 R2 R3 R4 R5 R6 NMR Salt 309 —H —Cl —F —H —H —(CH₂)₂OC₆H₅1H-NMR (DMSO-d6) δppm: 1.85-2.1 2 Hydro (1H, m), 2.1-2.3 (1H, m),2.95-3.25 chloride (2H, m), 3.25-3.55 (2H, m), 3.67 (2H, t, J = 5.5Hz),3.85-4.1 (3H, m), 4.4-4.6 (2H, m), 6.8-7.0 (4H, m), 7.1-7.2 (1H, m),7.2-7.35 (3H, m), 9.43 (1H, br), 9.60 (1H, br). 310 —H —Cl —F —H —H

1H-NMR (DMSO-d6) δppm: 1.8-1.95 (3H, m), 2.05-2.15 (1H, m), 2.6-3.95(11H, m), 4.07 (2H, t, J = 6Hz), 4.35- 4.45 (1H, m), 6.57 (4H, s),6.9-6.95 (1H, m), 7.12 (1H, dd, J = 3, 6.5Hz), 2 Fumarate 7.26 (1H, dd,J = 9, 9Hz), 7.32 (1H, dd, J = 4.5, 8.5Hz), 7.38 (1H, dd, J = 1.5,8.5Hz), 8.17 (1H, dd, J = 3.5, 3.5Hz), 8.31 (1H, d, J = 3Hz). 311 —H —Cl—F —H —H

1H-NMR (DMSO-d6) δppm: 1.45-1.55 (2H, m), 1.65-1.8 (2H, m), 1.8-1.95(1H, m), 2.05-2.15 (1H, m), 2.6-4.05 (11H, m), 4.25 (2H, t, J = 6.5Hz),4.3- 4.4 (1H, m), 6.55 (4H, s), 6.77 (1H, d, 2 Fumarate J = 8.5Hz),6.8-6.9 (1H, m), 6.9-7.0 (1H, m), 7.03 (1H, dd, J = 3, 6.5Hz), 7.22 (1H,dd, J = 9, 9Hz), 7.65-7.7 (1H, m), 8.1-8.15 (1H, m).

TABLE 87

Ex. No. R1 R2 R3 R4 R5 MS (M + 1) 312 —H —H —OC₂H₅ —H —H 283 313 —CH₃ —H—H —H —H 253 314 —H —H —CF₃ —H —H 307 315 —H —H —CN —H —H 264 316 —H—NO₂ —H —H —H 284 317 —H —H —NO₂ —H —H 284 318 —H —H —N(CH₃)₂ —H —H 282319 —H —CH₃ —H —H —H 253 320 —OCH₃ —H —H —H —H 269 321 —H —OCH₃ —H —H —H269 322 —H —OC₂H₆ —H —H —H 283 323 —H —OCF₃ —H —H —H 323 324 —H —SCH₃ —H—H —H 285 325 —H —N(CH₃)₂ —H —H —H 282 326 —CN —H —H —H —H 264 327 —H —H—SCH₃ —H —H 285 328 —H —CF₃ —H —H —H 307 329 —CH₃ —H —F —H —H 271 330 —H—CF₃ —Cl —H —H 341 331 —H —H —CH₃ —H —H 253 332 —H —Cl —H —H —H 307 333—H —H —COC₆H₅ —H —H 343 334 —H —H —CH(CH₃)₂ —H —H 281 335 —H —H —OC₆H₅—H —H 331 336 —H —H —OC₆H₁₃ —H —H 339 337 —H —H —C₂H₅ —H —H 267 338 —H—H —OCH₂C₈H₅ —H —H 345 339 —H —CF₃ —F —H —H 325 340 —H —CF₃ —H —CF₃ —H375 341 —H —H —OCH₃ —H —H 269 342 —CH₃ —CH₃ —H —H —H 267 343 —C₂H₆ —H —H—H —H 267 344 —H —F —H —H —OCH₃ 287 345 —H —H —COCH₃ —H —H 281 346 —H—COCH₃ —H —H —H 281 347 —CH₃ —H —Cl —H —H 287 348 —H —Cl —Cl —H —H 307

TABLE 88

MS Ex. (M + No. R1 R2 R3 R4 R5 1) 349 —H —F —F —H —H 275 350 —H —F —H —F—H 275 351 —H —H —CF₃ —F —H 325 352 —H —CF₃ —H —F —H 325 353 —H —CF₃—CH₃ —H —H 321 354 —H —SCF₃ —H —H —H 339 355 —H —CF₃ —OCH₃ —H —H 337 356—H —CH₃ —N(CH₃)₂ —CH₃ —H 310 357 —H —CH(CH₃)₂ —H —H —H 281 358 —H —H—SC₂H₅ —H —H 299 359 —H —H —N(C₂H₅)₂ —H —H 310 360 —H —OCH(CH₃)₂ —H —H—H 297 361 —H —F —H —Cl —H 291 362 —H —CH₃ —H —CH₃ —H 363 —H —F —CH₃ —H—H 271 364 —H —F —Cl —H —H 291 365 —H —C₈H₅ —H —H —H 315 366 —H —F —H —H—H 257 367 —H —Cl —CH₃ —H —H 287 368 —H —F —F —F —H 293 369 —H —F —H —H—CH₃ 271 370 —F —H —H —CH₃ —H 271 371 —H —F —OCH₃ —H —H 287 372 —H —CH₃—Cl —H —H 287 373 —H —H —C₃H₇ —H —H 281 374 —OCH₃ —H —H —CH₃ —H 283 375—CH₃ —Cl —H —H —H 287 376 —H —H —CH₂C₆H₅ —H —H 329 377 —H —Cl —H —H—OCH₃ 303 378 —CH₃ —F —CH₃ —H —H 285 379 —H —CH₂CH₂CN —H —H —H 292 380—H —H —CH₂CH₂CN —H —H 292 381 —H —Cl —H —H —CH₃ 287 382 —H —OCHF₂ —H —H—H 305 383 —H —C₂H₅ —H —H —H 267 384 —H —F —OCH₃ —F —H 305 385 —CH₃ —H—CH₃ —H —H 267

TABLE 89

MS Ex. (M + No. R1 R2 R3 R4 R5 1) 386 —H —F —F —OCH₃ —H 305 387 —H —Cl—H —H —H 273 388 —CH₃ —H —H —CH₃ —H 267 389 —H —CH₃ —CH₃ —H —H 267 390—H —OCH₃ —OCH₃ —OCH₃ —H 329 391 —H —CN —F —H —H 282 392 —CH(CH₃)₂ —H —H—CH₃ —H 295 393 —H —H —COC₂H₅ —H —H 295 394 —H —H —CF₃ —H —F 325 395 —F—H —CF₃ —F —H 343 396 —H —CO₂C₂H₅ —Cl —H —H 345 397 —CH₂C₈H₅ —H —H —H —H329 398 —H —CH₃ —OCH₃ —H —H 283 399 —H —H —C₆H₅ —H —H 315 400 —H —Cl —CN—H —H 298 401 —H —CH₃ —F —CH₃ —H 285 402 —H —H —OCF₂CHF₂ —H —H 355 403—H —H —OH —H —H 255

TABLE 90

Ex. No. R1 R2 R3 R4 R5 MS (M + 1) 404 —H —H

—H —H 322 405 —H

—H —H —H 336 406 —H —H

—H —H 306 407 —H —H

—H —H 305 408 —H —H

—H —H 352 409 —H —H

—H —H 306 410 —H —H

—H —H 307 411 —H

—H —H —H 349

TABLE 91

Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 MS (M + 1) 412 —H —Cl —F —H —H —H—H —OC₂H₅ —H —H 335 413 —H —Cl —F —H —H —CH₃ —H —H —H —H 305 414 —H —Cl—F —H —H —H —H —CF₃ —H —H 359 415 —H —Cl —F —H —H —H —H —CN —H —H 316416 —H —Cl —F —H —H —H —H —N(CH₃)₂ —H —H 334 417 —H —Cl —F —H —H —H —CH₃—H —H —H 305 418 —H —Cl —F —H —H —H —CO₂C₂H₅ —H —H —H 363 419 —H —Cl —F—H —H —OCH₃ —H —H —H —H 321 420 —H —Cl —F —H —H —H —OCH₃ —H —H —H 321421 —H —Cl —F —H —H —H —OC₂H₅ —H —H —H 335 422 —H —Cl —F —H —H —H —OCF₃—H —H —H 375 423 —H —Cl —F —H —H —H —SCH₃ —H —H —H 337 424 —H —CH₃ —F —H—H —H —H —OC₂H₅ —H —H 315 425 —H —CH₃ —F —H —H —CH₃ —H —H —H —H 285 426—H —CH₃ —F —H —H —H —H —CF₃ —H —H 339 427 —H —CH₃ —F —H —H —H —H —CN —H—H 296 428 —H —CH₃ —F —H —H —H —NO₂ —H —H —H 316 429 —H —CH₃ —F —H —H —H—H —NO₂ —H —H 316 430 —H —CH₃ —F —H —H —H —H —N(CH₃)₂ —H —H 314 431 —H—CH₃ —F —H —H —H —CH₃ —H —H —H 285 432 —H —CH₃ —F —H —H —OCH₃ —H —H —H—H 301 433 —H —CH₃ —F —H —H —H —OCH₃ —H —H —H 301 434 —H —CH₃ —F —H —H—H —OC₂H₅ —H —H —H 315 435 —H —CH₃ —F —H —H —H —OCF₃ —H —H —H 355 436 —H—CH₃ —F —H —H —H —SCH₃ —H —H —H 317 437 —H —H —F —H —H —H —H —OC₂H₅ —H—H 301 438 —CH₃ —H —H —H —H —H —H —F —H —H 271 439 —H —H —CF₃ —H —H —H—H —F —H —H 325 440 —H —H —F —H —H —H —H —CN —H —H 282 441 —H —NO₂ —H —H—H —H —H —F —H —H 302 442 —H —H —NO₂ —H —H —H —H —F —H —H 302 443 —H —H—N(CH₃)₂ —H —H —H —H —F —H —H 300 444 —H —CH₃ —H —H —H —H —H —F —H —H271 445 —OCH₃ —H —H —H —H —H —H —F —H —H 287 446 —H —OCH₃ —H —H —H —H —H—F —H —H 287

TABLE 92

Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 MS (M + 1) 447 —H —OC₂H₅ —H —H —H—H —H —F —H —H 301 448 —H —OCF₃ —H —H —H —H —H —F —H —H 341 449 —H —SCH₃—H —H —H —H —H —F —H —H 303 450 —H —N(CH₃)₂ —H —H —H —H —Cl —F —H —H 334451 —H —Cl —F —H —H —CN —H —H —H —H 316 452 —H —Cl —F —H —H —H —H —SCH₃—H —H 337 453 —H —N(CH₃)₂ —H —H —H —H —CH₃ —F —H —H 314 454 —H —CH₃ —F—H —H —H —H —SCH₃ —H —H 317 455 —H —N(CH₃)₂ —H —H —H —H —H —F —H —H 300456 —H —H —F —H —H —H —H —SCH₃ —H —H 303

TABLE 93

Ex. No. R1 R2 R3 R4 R5 R6 MS (M + 1) 457 —H —H —H —H —H

283 458 —H —H —H —H —H

283 459 —H —H —H —H —H

319 460 —H —Cl —F —H —H

349 461 —H —H —H —H —H

297 462 —H —CH₃ —F —H —H

329 463 —H —H —F —H —H

315 464 —H —H —H —H —H

369 465 —H —H —H —H —H

311 466 —H —H —H —H —H

369 467 —H —H —H —H —H

293

TABLE 94

Ex. No. R1 R2 R3 R4 R5 R6 MS (M + 1) 468 —H —H —H —H —H

289 469 —H —H —H —H —H

289 470 —H —H —H —H —H

319 471 —H —H —H —H —H

307 472 —H —H —H —H —H

327 473 —H —H —H —H —H

281 474 —H —H —H —H —H

279 475 —H —Cl —F —H —H

347 476 —H —H —H —H —H

295 477 —H —CH₃ —F —H —H

327 478 —H —H —F —H —H

313

TABLE 95

Ex. No. R1 R2 R3 R4 R5 R6 MS (M + 1) 479 —H —H —H —H —H

295 480 —H —Cl —F —H —H

297 481 —H —Cl —F —H —H

394 482 —H —H —H —H —H

321 483 —H —H —H —H —H

246 484 —H —Cl —F —H —H

298 485 —H —CH₃ —F —H —H

278 486 —H —H —H —H —H

243 487 —H —H —F —H —H

261

TABLE 96

Ex. No. R1 R2 R3 R4 R5 R6 MS (M + 1) 488 —H —H —H —H —H

255 489 —H —Cl —F —H —H

307 490 —H —CH₃ —F —H —H

287 491 —H —H —F —H —H

273 492 —H —CH₃ —F —H —H

303 493 —H —H —H —H —H

317 494 —H —Cl —F —H —H

369 495 —H —CH₃ —F —H —H

349

TABLE 97

Ex. No. R1 R2 R3 R4 R5 R6 MS (M + 1) 496 —H —H —H —H —H

241 497 —H —Cl —F —H —H

293 498 —H —CH₃ —F —H —H

273 499 —H —H —H —H —H

269 500 —H —H —F —H —H

287 501 —H —CH₃ —F —H —H

301 502 —H —Cl —F —H —H

321 503 —H —H —H —H —H

283 504 —H —Cl —F —H —H

335 505 —H —H —F —H —H

301 506 —H —CH₃ —F —H —H

315

TABLE 98

MS Ex. (M + No. R1 R2 R3 R4 R5 R6 1) 507 —H —H —H —H —H

269 508 —H —Cl —F —H —H

321 509 —H —CH₃ —F —H —H

301 510 —H —H —F —H —H

287 511 —H —Cl —F —H —H

361 512 —H —CH₃ —F —H —H

341 513 —H —H —F —H —H

327 514 —H —H —H —H —H

301 515 —H —Cl —F —H —H

353 516 —H —CH₃ —F —H —H

333

TABLE 99

Ex. No. R1 R2 R3 R4 R5 R6 MS (M + 1) 517 —H —H —F —H —H

319 518 —H —H —H —H —H

287 519 —H —Cl —F —H —H

339 520 —H —CH₃ —F —H —H

319 521 —H —H —F —H —H

305 522 —H —Cl —F —H —H

411 523 —H —CH₃ —F —H —H

391

TABLE 100

Ex. No. R1 R2 R3 R4 R5 R6 MS (M + 1) 524 —H —Cl —F —H —H

353 525 —H —H —H —H —H

337 526 —H —CH₃ —F —H —H

369 527 —H —H —F —H —H

399 528 —H —CH₃ —F —H —H

413 529 —H —H —H —H —H

241 530 —H —CH₃ —F —H —H

273 531 —H —H —F —H —H

259 532 —H —Cl —F —H —H

293

TABLE 101

Ex. No. R1 R2 R3 R4 R5 R6 MS (M + 1) 533 —H —H —H —H —H

241 534 —H —Cl —F —H —H

293 535 —H —CH₃ —F —H —H

273 536 —H —H —F —H —H

259 537 —H —H —H —H —H

269 538 —H —Cl —F —H —H

321 539 —H —CH₃ —F —H —H

301 540 —H —H —F —H —H

287 541 —H —H —H —H —H

271 542 —H —Cl —F —H —H

323 543 —H —CH₃ —F —H —H

303

TABLE 102

Ex. No. R1 R2 R3 R4 R5 R6 MS (M + 1) 544 —H —H —F —H —H

289 545 —H —H —H —H —H

322 546 —H —H —H —H —H

296 547 —H —Cl —F —H —H

348 548 —H —CH₃ —F —H —H

328 549 —H —H —F —H —H

314 550 —H —H —H —H —H

326 551 —H —Cl —F —H —H

378 552 —H —CH₃ —F —H —H

358 553 —H —H —F —H —H

344 554 —H —H —H —H —H

310

TABLE 103

Ex. No. R1 R2 R3 R4 R5 R6 MS (M + 1) 555 —H —H —H —H —H

296 556 —H —H —H —H —H

296 557 —H —H —H —H —H

296 558 —H —Cl —F —H —H

348 559 —H —CH₃ —F —H —H

328 560 —H —H —F —H —H

314 561 —H —H —H —H —H

297 562 —H —Cl —F —H —H

349 563 —H —CH₃ —F —H —H

329 564 —H —H —F —H —H

315 565 —H —H —H —H —H

311

TABLE 104

Ex. No. R1 R2 R3 R4 R5 R6 MS (M + 1) 566 —H —Cl —F —H —H

363 567 —H —CH₃ —F —H —H

343 568 —H —H —F —H —H

329 569 —H —H —F —H —H

315 570 —H —Cl —F —H —H

363 571 —H —CH₃ —F —H —H

343 572 —H —H —F —H —H

329 573 —H —H —H —H —H

387 574 —H —Cl —F —H —H

439

TABLE 105

Ex. No. R1 R2 R3 R4 R5 R6 MS (M + 1) 575 —H —CH₃ —F —H —H

419 576 —H —H —H —H —H

322 577 —H —Cl —F —H —H

374 578 —H —CH₃ —F —H —H

354 579 —H —H —F —H —H

340 580 —H —H —H —H —H

290 581 —H —Cl —F —H —H

342 582 —H —CH₃ —F —H —H

322 583 —H —H —F —H —H

308

TABLE 106

Ex. No. R1 R2 R3 R4 R5 R6 MS (M + 1) 584 —H —H —H —H —H

290 585 —H —H —F —H —H

308 586 —H —Cl —F —H —H

342 587 —H —H —H —H —H

290 588 —H —H —H —H —H

304 589 —H —H —H —H —H

310 590 —H —H —H —H —H

354 591 —H —H —H —H —H

291 592 —H —Cl —F —H —H

343 593 —H —CH₃ —F —H —H

323 594 —H —H —H —H —H

291

TABLE 107

Ex. No. R1 R2 R3 R4 R5 R6 MS (M + 1) 595 —H —H —H —H —H

367 596 —H —Cl —F —H —H

419 597 —H —CH₃ —F —H —H

399 598 —H —H —F —H —H

385

TABLE 108

Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 MS (M + 1) 599 —H —Cl —F —H —H —H—NO₂ —H —H 337 600 —H —Cl —F —H —H —H —CO₂CH₃ —H —H 350 601 —H —Cl —F —H—H —H —H —H —CF₃ 360 602 —H —Cl —F —H —H —H —Cl —H —H 326 603 —H —Cl —F—H —H —H —H —H —Cl 326 604 —H —Cl —F —H —H —OCH₃ —H —H —H 322 605 —H —Cl—F —H —H —H —H —H —H 292 606 —H —Cl —F —H —H —H —CH₃ —H —H 306 607 —H—Cl —F —H —H —H —H —CH₃ —H 306 608 —H —Cl —F —H —H —H —H —CF₃ —H 360 609—H —Cl —F —H —H —CH₃ —H —H —H 306 610 —H —Cl —F —H —H —H —CF₃ —H —H 360611 —H —H —H —H —H —H —NO₂ —H —H 285 612 —H —H —H —H —H —H —CO₂CH₃ —H —H298 613 —H —H —H —H —H —H —H —H —CF₃ 308 614 —H —H —H —H —H —H —Cl —H —H274 615 —H —H —H —H —H —H —H —H —Cl 274 616 —H —H —H —H —H —H —H —H —H240 617 —H —H —H —H —H —H —CH₃ —H —H 254 618 —H —H —H —H —H —H —H —CH₃—H 254 619 —H —H —H —H —H —H —H —CF₃ —H 308 620 —H —H —H —H —H —CH₃ —H—H —H 254 621 —H —H —H —H —H —OCH₃ —H —H —H 270 622 —H —H —H —H —H —H —H—H —CH₃ 254 623 —H —H —H —H —H —H —CF₃ —H —H 308 624 —H —CH₃ —F —H —H —H—NO₂ —H —H 317 625 —H —CH₃ —F —H —H —H —CO₂CH₃ —H —H 330 626 —H —CH₃ —F—H —H —H —H —H —CF₃ 340 627 —H —CH₃ —F —H —H —H —H —H —NO₂ 317 628 —H—CH₃ —F —H —H —H —Cl —H —H 306 629 —H —CH₃ —F —H —H —H —H —H —Cl 306 630—H —CH₃ —F —H —H —H —H —H —H 272 631 —H —CH₃ —F —H —H —H —CH₃ —H —H 286632 —H —CH₃ —F —H —H —H —H —CH₃ —H 286 633 —H —CH₃ —F —H —H —H —H —CF₃—H 340 634 —H —CH₃ —F —H —H —CH₃ —H —H —H 286 635 —H —CH₃ —F —H —H —OCH₃—H —H —H 302

TABLE 109

Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 MS (M + 1) 636 —H —CH₃ —F —H —H —H —H—H —CH₃ 286 637 —H —CH₃ —F —H —H —H —CF₃ —H —H 340 638 —H —H —F —H —H —H—NO₂ —H —H 303 639 —H —H —F —H —H —H —CO₂CH₃ —H —H 316 640 —H —H —F —H—H —H —H —H —CF₃ 326 641 —H —H —F —H —H —H —Cl —H —H 292 642 —H —H —F —H—H —H —H —H —Cl 292 643 —H —H —F —H —H —H —H —H —H 258 644 —H —H —F —H—H —H —CH₃ —H —H 272 645 —H —H —F —H —H —H —H —CH₃ —H 272 646 —H —H —F—H —H —H —H —CF₃ —H 326 647 —H —H —F —H —H —CH₃ —H —H —H 272 648 —H —H—F —H —H —OCH₃ —H —H —H 288 649 —H —H —F —H —H —H —CF₃ —H —H 326 650 —H—Cl —F —H —H —CH₃ —H —CF₃ —H 374 651 —H —Cl —F —H —H —H —H —NO₂ —H 337652 —H —Cl —F —H —H —H —H —OCH₃ —H 322 653 —H —Cl —F —H —H —H —H —C₂H₅—H 320 654 —H —H —H —H —H —CH₃ —H —CF₃ —H 322 655 —H —H —H —H —H —H —H—NO₂ —H 285 656 —H —H —H —H —H —H —H —OCH₃ —H 270 657 —H —H —H —H —H —H—H —C₂H₅ —H 268 658 —H —CH₃ —F —H —H —CH₃ —H —CF₃ —H 354 659 —H —CH₃ —F—H —H —H —H —NO₂ —H 317 660 —H —CH₃ —F —H —H —H —H —OCH₃ —H 302 661 —H—CH₃ —F —H —H —H —H —C₂H₅ —H 300 662 —H —H —F —H —H —CH₃ —H —CF₃ —H 340663 —H —H —F —H —H —H —H —NO₂ —H 303 664 —H —H —F —H —H —H —H —OCH₃ —H288 665 —H —H —F —H —H —H —H —C₂H₅ —H 286

TABLE 110

Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 MS (M + 1) 666 —H —H —H —H —H —H —H

—H 309

TABLE 111

Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 MS (M + 1) 667 —H —Cl —F —H —H —H —H—H —H 292 668 —H —H —H —H —H —H —H —H —H 240 669 —H —H —H —H —H —H —NO₂—H —H 285 670 —H —H —H —H —H —CH₃ —CH₃ —H —H 268 671 —H —CH₃ —F —H —H —H—H —H —H 272 672 —H —CH₃ —F —H —H —H —NO₂ —H —H 317 673 —H —H —F —H —H—H —H —H —H 258 674 —H —H —F —H —H —H —NO₂ —H —H 303 675 —H —H —F —H —H—CH₃ —CH₃ —H —H 286 676 —H —Cl —F —H —H —H —CH₃ —H —H 306 677 —H —Cl —F—H —H —H —OCH₃ —H —H 322 678 —H —Cl —F —H —H —H —H —OCH₃ —H 322 679 —H—H —H —H —H —H —CH₃ —H —H 254 680 —H —H —H —H —H —H —H —OCH₃ —H 270 681—H —CH₃ —F —H —H —H —CH₃ —H —H 286 682 —H —CH₃ —F —H —H —H —H —OCH₃ —H302 683 —H —H —F —H —H —H —CH₃ —H —H 272 684 —H —H —F —H —H —H —H —OCH₃—H 288 685 —H —H —OC₂H₅ —H —H —H —H —H —H 284 686 —CH₃ —H —H —H —H —H —H—H —H 254 687 —H —H —CF₃ —H —H —H —H —H —H 308 688 —H —H —CN —H —H —H —H—H —H 265 689 —H —NO₂ —H —H —H —H —H —H —H 285 690 —H —H —NO₂ —H —H —H—H —H —H 285 691 —H —H —N(CH₃)₂ —H —H —H —H —H —H 283 692 —H —CF₃ —H —H—H —H —H —H —H 308 693 —CH₃ —H —F —H —H —H —H —H —H 272 694 —H —CF₃ —Cl—H —H —H —H —H —H 342 695 —H —H —CH₃ —H —H —H —H —H —H 254 696 —H —H—C(CH₃)₃ —H —H —H —H —H —H 296 697 —H —Cl —H —Cl —H —H —H —H —H 308 698—H —H —SCH₃ —H —H —H —H —H —H 286 699 —H —H —COC₆H₅ —H —H —H —H —H —H344 700 —H —H —CH(CH₃)₂ —H —H —H —H —H —H 282 701 —H —H —OC₆H₅ —H —H —H—H —H —H 332 702 —H —H —OC₆H₁₃ —H —H —H —H —H —H 340 703 —H —H —C₆H₁₃ —H—H —H —H —H —H 324 704 —H —H —C₂H₅ —H —H —H —H —H —H 268

TABLE 112

Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 MS (M + 1) 705 —H —H —OCH₂C₆H₅ —H —H—H —H —H —H 346 706 —H —CF₃ —F —H —H —H —H —H —H 326 707 —H —CF₃ —H —CF₃—H —H —H —H —H 376 708 —H —OCH₃ —H —H —OCH₃ —H —H —H —H 300 709 —Cl —H—H —H —H —H —H —H —H 274 710 —H —H —OCH₃ —H —H —H —H —H —H 270 711 —CH₃—CH₃ —H —H —H —H —H —H —H 268 712 —C₂H₅ —H —H —H —H —H —H —H —H 268 713—H —F —H —H —OCH₃ —H —H —H —H 288 714 —H —H —COCH₃ —H —H —H —H —H —H 282715 —H —COCH₃ —H —H —H —H —H —H —H 282 716 —CH₃ —H —Cl —H —H —H —H —H —H288 717 —H —Cl —Cl —H —H —H —H —H —H 308 718 —H —F —F —H —H —H —H —H —H276 719 —H —F —H —F —H —H —H —H —H 276 720 —H —H —CF₃ —F —H —H —H —H —H326 721 —H —CF₃ —H —F —H —H —H —H —H 326 722 —H —CF₃ —CH₃ —H —H —H —H —H—H 322 723 —H —SCF₃ —H —H —H —H —H —H —H 340 724 —H —CF₃ —OCH₃ —H —H —H—H —H —H 338 725 —H —CH₃ —N(CH₃)₂ —CH₃ —H —H —H —H —H 311 726 —H—CH(CH₃)₂ —H —H —H —H —H —H —H 282 727 —H —H —SC₂H₅ —H —H —H —H —H —H300 728 —H —H —N(C₂H₅)₂ —H —H —H —H —H —H 311 729 —H —OCH(CH₃)₂ —H —H —H—H —H —H —H 298 730 —H —H —OCHF₂ —H —H —H —H —H —H 306 731 —H —F —H —Cl—H —H —H —H —H 292 732 —H —CH₃ —OCH₃ —CH₃ —H —H —H —H —H 298 733 —H —CH₃—H —CH₃ —H —H —H —H —H 268 734 —H —F —CH₃ —H —H —H —H —H —H 272 735 —H—F —Cl —H —H —H —H —H —H 292 736 —H —C₆H₅ —H —H —H —H —H —H —H 316 737—H —F —H —H —H —H —H —H —H 258 738 —H —Cl —CH₃ —H —H —H —H —H —H 288 739—H —F —F —F —H —H —H —H —H 294 740 —H —F —H —H —CH₃ —H —H —H —H 272 741—F —H —H —CH₃ —H —H —H —H —H 272 742 —H —F —OCH₃ —H —H —H —H —H —H 288

TABLE 113

Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 MS (M + 1) 743 —H —CH₃ —Cl —H —H —H—H —H —H 288 744 —H —H —C₃H₇ —H —H —H —H —H —H 282 745 —OCH₃ —H —H —CH₃—H —H —H —H —H 284 746 —CH₃ —Cl —H —H —H —H —H —H —H 288 747 —H —H—CH₂C₆H₅ —H —H —H —H —H —H 330 748 —H —Cl —H —H —OCH₃ —H —H —H —H 304749 —CH₃ —F —CH₃ —H —H —H —H —H —H 286 750 —H —CH₂CH₂CN —H —H —H —H —H—H —H 293 751 —H —H —CH₂CH₂CN —H —H —H —H —H —H 293 752 —H —Cl —H —H—CH₃ —H —H —H —H 288 753 —H —OCHF₂ —H —H —H —H —H —H —H 306 754 —H —C₂H₅—H —H —H —H —H —H —H 268 755 —H —F —OCH₃ —F —H —H —H —H —H 306 756 —H —F—F —H —OCH₃ —H —H —H —H 306 757 —CH₃ —H —CH₃ —H —H —H —H —H —H 268 758—H —F —F —OCH₃ —H —H —H —H —H 306 759 —H —OCH₃ —OCH₃ —H —H —H —H —H —H300 760 —H —Cl —H —H —H —H —H —H —H 274 761 —CH₃ —H —H —CH₃ —H —H —H —H—H 268 762 —H —CH₃ —CH₃ —H —H —H —H —H —H 268 763 —H —CN —F —H —H —H —H—H —H 283 764 —CH(CH₃)₂ —H —H —CH₃ —H —H —H —H —H 296 765 —H —NO₂ —F —H—H —H —H —H —H 303 766 —CH₂C₆H₅ —H —H —H —H —H —H —H —H 330 767 —H —CH₃—OCH₃ —H —H —H —H —H —H 284 768 —H —H —C₆H₅ —H —H —H —H —H —H 316 769 —H—Cl —CN —H —H —H —H —H —H 299 770 —H —CH₃ —F —CH₃ —H —H —H —H —H 286 771—H —H —OCF₂CHF₂ —H —H —H —H —H —H 356 772 —H —H —OH —H —H —H —H —H —H256

TABLE 114

Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 MS (M + 1) 773 —H

—H —H —H —H —H —H —H 337 774 —H —H

—H —H —H —H —H —H 307 775 —H —H

—H —H —H —H —H —H 353 776 —H —H

—H —H —H —H —H —H 308 777 —H

—H —H —H —H —H —H —H 350

TABLE 115

Ex. No. R1 MS (M + 1) 778

296 779

298 780

290 781

311 782

290 783

284 784

294 785

312 786

291 787

292 788

311

TABLE 116

Ex. No. R1 MS (M + 1) 789

284 790

282 791

305 792

370 793

370 794

320 795

320 796

323 797

308 798

328 799

280

TABLE 117

Ex. No. R1 MS (M + 1) 800

279 801

353 802

355 803

310 804

297 805

297

TABLE 118

Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 MS (M + 1) 806 —H —Cl —F —H —H —H —H—CH₃ —H 306 807 —H —Cl —F —H —H —H -2-PYRIDYL -2-PYRIDYL —H 446 808 —H—H —H —H —H —H —H —CH₃ —H 254 809 —H —H —H —H —H —H —H —H —CH₃ 254 810—H —H —H —H —H —H -2-PYRIDYL -2-PYRIDYL —H 394 811 —H —CH₃ —F —H —H —H—H —CH₃ —H 286 812 —H —CH₃ —F —H —H —H -2-PYRIDYL -2-PYRIDYL —H 426 813—H —H —F —H —H —H -2-PYRIDYL -2-PYRIDYL —H 412

TABLE 119

Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11 MS (M + 1) 814 —H —Cl —F —H—H —H —H —H —H —H —H 342 815 —H —H —H —H —H —H —H —H —H —H —H 290 816 —H—CH₃ —F —H —H —H —H —H —H —H —H 322 817 —H —H —F —H —H —H —H —H —H —H —H308

TABLE 120

Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11 MS (M+1) 818 —H —Cl —F —H —H—CH₃ —H —H —H —H —H 356 819 —H —Cl —F —H —H —H —H —H —H —H —H 342 820 —H—Cl —F —H —H —H —H —H —H —CF₃ —H 410 821 —H —Cl —F —H —H —C₆H₅ —H —H —H—H —H 418 822 —H —Cl —F —H —H —H —H —H —H —Cl —H 376 823 —H —Cl —F —H —H—CF₃ —H —H —H —H —H 410 824 —H —Cl —F —H —H —H —H —H —H —H —CF₃ 410 825—H —H —H —H —H —CH₃ —H —H —H —H —H 304 826 —H —H —H —H —H —H —H —H —H —H—H 290 827 —H —H —H —H —H —H —H —H —H —CF₃ —H 358 828 —H —H —H —H —H—C₆H₅ —H —H —H —H —H 366 829 —H —H —H —H —H —H —H —H —H —Cl —H 324 830—H —H —H —H —H —CF₃ —H —H —H —H —H 358 831 —H —H —H —H —H —H —H —H —H —H—CF₃ 358 832 —H —CH₃ —F —H —H —CH₃ —H —H —H —H —H 336 833 —H —CH₃ —F —H—H —H —H —H —H —H —H 322 834 —H —CH₃ —F —H —H —H —H —H —H —CF₃ —H 390835 —H —CH₃ —F —H —H —C₆H₅ —H —H —H —H —H 398 836 —H —CH₃ —F —H —H —H —H—H —H —Cl —H 356 837 —H —CH₃ —F —H —H —CF₃ —H —H —H —H —H 390 838 —H—CH₃ —F —H —H —H —H —H —H —H —CF₃ 390 839 —H —H —F —H —H —CH₃ —H —H —H—H —H 322 840 —H —H —F —H —H —H —H —H —H —H —H 308 841 —H —H —F —H —H —H—H —H —H —CF₃ —H 376 842 —H —H —F —H —H —C₆H₅ —H —H —H —H —H 384 843 —H—H —F —H —H —H —H —H —H —Cl —H 342 844 —H —H —F —H —H —CF₃ —H —H —H —H—H 376 845 —H —H —F —H —H —H —H —H —H —H —CF₃ 376 846 —H —Cl —F —H —H —H—H —H —CF₃ —H —H 410 847 —H —H —H —H —H —H —H —H —F —H —F 326 848 —H —H—H —H —H —H —H —H —CF₃ —H —H 358 849 —H —CH₃ —F —H —H —H —H —H —F —H —F358 850 —H —CH₃ —F —H —H —H —H —H —CF₃ —H —H 390 851 —H —H —F —H —H —H—H —H —F —H —F 344 852 —H —H —F —H —H —H —H —H —CF₃ —H —H 376 853 —H —H—H —H —H —OCH₃ —H —H —H —H —H 320

TABLE 121

Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11 MS (M + 1) 854 —H —H —F —Cl—H —H —H —H —H —H —H 342 855 —H —H —F —Cl —H —CH₃ —H —H —H —H —H 356 856—H —H —F —Cl —H —OCH₃ —H —H —H —H —H 372 857 —H —H —F —Cl —H —H —CH₃ —H—H —H —H 356 858 —H —H —F —Cl —H —H —H —NO₂ —H —H —F 405 859 —H —H —F—Cl —H —CH₂C₆H₅ —H —H —H —H —H 432 860 —H —H —F —Cl —H —H —H —H —OCH₃ —H—H 372 861 —H —H —F —Cl —H —H —OCH₃ —H —H —H —H 372 862 —H —H —F —Cl —H—H —H —H —H —OCH₃ —H 372 863 —H —H —H —H —H —H —H —H —H —H —H 290 864 —H—H —H —H —H —CH₃ —H —H —H —H —H 304 865 —H —H —H —H —H —OCH₃ —H —H —H —H—H 320 866 —H —H —H —H —H —H —CH₃ —H —H —H —H 304 867 —H —H —H —H —H —H—H —NO₂ —H —H —F 353 868 —H —H —H —H —H —CH₂C₆H₅ —H —H —H —H —H 380 869—H —H —H —H —H —H —H —H —OCH₃ —H —H 320 870 —H —H —H —H —H —H —OCH₃ —H—H —H —H 320 871 —H —H —H —H —H —H —H —H —H —OCH₃ —H 320 872 —H —H —F—CH₃ —H —H —H —H —H —H —H 322 873 —H —H —F —CH₃ —H —CH₃ —H —H —H —H —H336 874 —H —H —F —CH₃ —H —OCH₃ —H —H —H —H —H 352 875 —H —H —F —CH₃ —H—H —CH₃ —H —H —H —H 336 876 —H —H —F —CH₃ —H —H —H —NO₂ —H —H —F 385 877—H —H —F —CH₃ —H —H —H —H —OCH₃ —H —H 352 878 —H —H —F —CH₃ —H —H —H —H—H —OCH₃ —H 352 879 —H —H —F —H —H —H —H —H —H —H —H 308 880 —H —H —F —H—H —CH₃ —H —H —H —H —H 322 881 —H —H —F —H —H —OCH₃ —H —H —H —H —H 338882 —H —H —F —H —H —H —CH₃ —H —H —H —H 322 883 —H —H —F —H —H —H —H —NO₂—H —H —F 371 884 —H —H —F —H —H —H —H —H —OCH₃ —H —H 338 885 —H —H —F —H—H —H —OCH₃ —H —H —H —H 338 886 —H —H —F —H —H —H —H —H —H —OCH₃ —H 338887 —H —H —H —H —H —H —OC₂H₅ —H —H —H —H 334

TABLE 122

Ex. No. R1 R2 R3 R4 R5 R6 MS (M + 1) 888 —H —H —F —H —H

297 889 —H —H —F —Cl —H —CH₂C≡CH 253 890 —H —H —F —Cl —H

415 891 —H —H —F —Cl —H

345 892 —H —H —F —Cl —H

346

TABLE 123

Ex. No. R1 R2 R3 R4 R5 R6 NMR Salt 893 —H —H —F —Cl —H

¹H-NMR (DMSO-d₆) δ ppm: 1.55-1.75 (1H, m), 2.2-2.35 (1H, m), 2.38 (6H,s), 2.85-3.0 (1H, m), 3.1-3.2 (2H, m), 3.6- 3.75 (1H, m), 4.17 (1H, br),4.77 (1H, tt, J = 7.7, 7.7 Hz), 7.21 (1H, dt, J = 4.0, 7.1 Hz),7.25-7.35 (1H, m), 7.55-7.65 (2H, m), 7.86 (1H, bs), 8.14 (1H, d, J =2.3 Hz), 8.76 (2H, br). 2Methanesulfonate 894 —H —H —F —Cl —H

¹H-NMR (DMSO-d₆) δ ppm: 1.55-1.75 (1H, m), 2.15-2.3 (1H, m), 2.8-3.0(1H, m), 3.05-3.2 (2H, m), 3.61 (1H, dd, J = 7.1, 11.8), 4.74 (1H, tt, J= 7.5, 7.5 Hz, 7.10 (1H, ddd, J = 2.4, 2.4, 12.0 Hz), 7.25-7.35 (1H, m),7.45-7.65 (2H, m), 7.82 (1H, s), 8.05 (1H, d, J = 2.2 Hz), 9.1-9.55 (2H,m). Hydrochloride 895 —H —H —F —CH₃ —H

¹H-NMR (DMSO-d₆) δ ppm: 1.55-1.75 (1H, m), 2.15-2.35 (4H, m), 2.75-2.95(1H, m), 3.0-3.2 (2H, m), 3.55-3.7 (1H, m), 4.76 (1H, tt, J = 7.6, 7.6Hz), 5.38 (1H, br), 7.05-7.25 (2H, m), 7.25-7.4 (2H, m), 7.75 (1H, dd, J= 1.2, 2.3 Hz), 8.07 (1H, d, J = 1.8 Hz), 9.43 (2H, br). 2Hydrochloride896 —H —H —F —Cl —H

¹H-NMR (DMSO-d₆) δ ppm: 1.55-1.75 (1H, m), 2.15-2.3 (1H, m), 2.8-3.0(1H, m), 3.0-3.2 (2H, m), 3.55-3.7 (1H, m), 4.75 (1H, tt, J = 7.6, 7.6Hz), 5.04 (1H, br), 6.9-7.05 (1H, m), 7.3-7.5 (2H, m), 7.62 (1H, dd, J =9.0, 9.0 Hz), 7.71 (1H, dd, J = 2.4, 6.7 Hz), 7.95-8.15 (2H, m), 9.40(2H, br). 2Hydrochloride

TABLE 124

Ex. No. R1 R2 R3 R4 R5 R6 NMR Salt 897 —H —H —F —Cl —H

¹H-NMR (DMSO-d₆) δ ppm: 1.5-1.7 (1H, m), 2.15-2.3 (1H, m), 2.8-2.95 (1H,m), 3.0-3.2 (2H, m), 3.5-3.65 (1H, m), 4.39 (1H, br), 4.70 (1H, tt, J =7.8, 7.8 Hz), 6.68 (1H, d, J = 11.3 Hz), 7.35-7.45 (1H, m), 7.46 (1H,s), 7.61 (1H, dd, J = 9.0, 9.0 Hz), 7.71 (1H, dd, J = 2.6, 6.8 Hz),7.95-8.05 (1H, m), 9.27 (2H, br). 2Hydrochloride 898 —H —H —F —Cl —H

¹H-NMR (DMSO-d₆) δ ppm: 1.55-1.75 (1H, m), 2.05-2.3 (1H, m), 2.8-3.0(1H, m), 3.05-3.3 (2H, m), 3.5-3.7 (1H, m), 4.78 (1H, tt, J = 7.3, 7.3Hz), 6.8-6.9 (1H, m), 7.1-7.2 (2H, m), 7.34 (1H, dd, J = 9.0, 9.0 Hz,7.44 (1H, d, J = 2.1 Hz), 7.97 (1H, s), 8.08 (1H, d, J = 8.7 Hz), 9.29(1H, br), 9.44 (1H, br). Hydrochloride 899 —H —H —F —H —H

¹H-NMR (DMSO-d₆) δ ppm: 1.55-1.75 (1H, m), 2.1-2.25 (1H, m), 2.85-3.05(1H, m), 3.1-3.25 (2H, m), 3.6-3.75 (1H, m), 3.8-5.0 (1H, m), 5.28 (1H,tt, J = 8.2, 8.2 Hz), 6.06 (1H, d, J = 8.9 Hz), 7.22 (1H, d, J = 5.9Hz), 7.35-7.5 (5H, m), 7.85 (1H, d, J = 8.9 Hz), 9.34 (2H, br).2Hydrochloride 900 —H —H —H —H —H

¹H-NMR (DMSO-d₆) δ ppm: 1.55-1.8 (1H, m), 2.2-2.35 (1H, m), 2.8-2.95(1H, m), 3.0-3.25 (2H, m), 3.6-3.75 (1H, m), 4.10 (1H, br), 4.75-4.9(1H, m), 6.68 (1H, dd, J = 2.1, 8.9 Hz), 7.15-7.3 (2H, m), 7.3-7.45 (1H,m), 7.45-7.6 (3H, m), 7.93 (1H, d, J = 8.9 Hz), 8.87 (1H, s), 9.26 (1H,br), 9.38 (1H, br). 2Hydrochloride

TABLE 125

Ex. No. R1 R2 R3 R4 R5 R6 NMR Salt 901 —H —H —F —H —H

¹H-NMR (DMSO-d₆) δ ppm: 1.6-1.75 (1H, m), 2.2-2.35 (1H, m), 2.8-2.95(1H, m), 3.05-3.25 (2H, m), 3.6-3.75 (1H, m), 4.47 (1H, br), 4.80 (1H,tt, J = 7.6, 7.6 Hz), 6.66 (1H, dd, J = 2.2, 8.9 Hz), 7.25-7.4 (4H, m),7.48 (1H, d, J = 1.8 Hz), 7.92 (1H, d, J = 9.0 Hz), 8.85 (1H, s), 9.34(1H, br), 9.45 (1H, br). 2Hydrochloride 902 —H —H —H —H —H

¹H-NMR (DMSO-d₆) δ ppm: 1.6-1.75 (1H, m), 2.15-2.3 (1H, m), 2.90 (1H,dd, J = 8.0, 11.6 Hz), 3.05-3.2 (2H, m), 3.62 (1H, dd, J = 6.9, 11.6Hz), 4.7-4.85 (1H, m), 6.92 (1H, d, J = 1.8 Hz), 7.04 (2H, d, J = 7.7Hz), 7.17 (1H, dd, J = 7.3, 7.3 Hz), 7.35-7.45 (3H, m), 7.63 (1H, d, J =1.3 Hz), 7.76 (1H, d, J = 5.5 Hz), 9.23 (2H, br). Hydrochloride 903 —H—H —H —H —H

¹H-NMR (DMSO-d₆) δ ppm: 1.6-1.75 (1H, m), 2.1-2.25 (1H, m), 2.55 (3H, d,J = 0.9 Hz, 2.8-2.95 (1H, m), 3.0-3.25 (2H, m), 3.5-3.65 (1H, m), 4.72(1H, tt, J = 7.3, 7.3 Hz), 6.80 (2H, d, J = 7.7 Hz), 6.85-7.0 (2H, m),7.10 (1H, s), 7.2-7.3 (2H, m), 7.63 (1H, d, J = 1.9 Hz), 7.69 (1H, d, J= 8.5 Hz), 9.17 (1H, br), 9.34 (1H, br). Hydrochloride 904 —H —H —F —H—H

¹H-NMR (DMSO-d₆) δ ppm: 1.6-1.75 (1H, m), 2.1-2.25 (1H, m), 2.53 (3H, d,J = 0.7 Hz), 2.8-2.95 (1H, m), 3.0-3.25 (2H, m), 3.5-3.65 (1H, m), 4.69(1H, tt, J = 7.1, 7.1 Hz), 6.86 (1H, dd, J = 2.1, 8.5 Hz), 6.9- 7.05(2H, m), 7.05 (1H, s), 7.1-7.2 (2H, m), 7.54 (1H, d, J = 1.9 Hz), 7.62(1H, d, J = 8.6 Hz), 9.30 (1H, br), 9.45 (1H, br). Hydrochloride

TABLE 126

Ex. No. R1 R2 R3 R4 R5 R6 NMR Salt 905 —H —H —CH₃ —F —H

¹H-NMR (DMSO-d₆) δ ppm: 1.58-1.71 (1H, m), 2.12 (3H, s), 2.19-2.23 (1H,m), 2.55 (2H, dd, J = 7.0, 8.0 Hz, with DMSO-d6), 2.78-2.89 (1H, m),2.86 (2H, dd, J = 7.0, 8.0 Hz), 3.08-3.22 (2H, m), 3.27 (3H, s),3.48-3.62 (1H, m, with H2O), 4.59-4.69 (1H, m), 6.44 (1H, dd, J = 2.3,8.3 Hz), 6.52 (1H, dd, J = 2.3, 12.8 Hz, 7.02-7.16 (4H, m), 9.34 (2H,br). Hydrochloride 906 —H —H —CH₃ —F —H

¹H-NMR (DMSO-d₆) δ ppm: 1.59-1.72 (1H, m), 2.13 (3H, d, J = 0.86 Hz),2.17-2.27 (1H, m), 2.82-2.91 (1H, m), 3.09-3.20 (2H, m), 3.61-3.63 (1H,m, with H2O), 3.63 (3H, s), 4.66-4.73 (1H, m), 6.47 (1H, dd, J = 2.3,8.5 Hz), 6.58 (1H, dd, J = 2.3, 12.6 Hz), 6.65 (1H, d, J = 9.5 Hz), 7.11(1H, dd, J = 8.5, 8.9 Hz), 7.36 (1H, dd, J = 2.5, 8.9 Hz), 7.56-7.60(2H, m), 7.89 (1H, d, J = 9.5 Hz), 9.33 (1H, br), 9.41 (1H, br).Hydrochloride 907 —H —H —F —CH₃ —H

¹H-NMR (DMSO-d₆) δ ppm: 1.59-1.72 (1H, m), 2.09-2.19 (1H, m), 2.19 (3H,d, J = 1.4 Hz), 2.48-2.51 (2H, m, with DMSO-d6), 2.78-2.90 (1H, m), 2.81(2H, dd, J = 6.8, 8.0 Hz), 3.09-3.19 (2H, m), 3.22 (3H, s), 3.40-3.54(1H, m, with H2O), 4.56-4.66 (1H, m), 6.75-6.80 (1H, m), 6.83-6.85 (2H,m), 6.90 (1H, dd, J = 2.6, 6.8 Hz), 7.02-7.11 (2H, m), 9.29 (1H, br),9.40 (1H, br). Hydrochloride 908 —H —H —F —CH₃ —H

¹H-NMR (DMSO-d₆) δ ppm: 1.62-1.75 (1H, m), 2.14-2.26 (1H, m), 2.20 (3H,d, J = 1.6 Hz), 2.85-2.95 (1H, m), 3.11- 3.43 (2H, m), 3.53-3.69 (1H, m,with H2O), 3.59 (3H, s), 4.64-4.73 (1H, m), 6.61 (1H, d, J = 9.4 Hz),6.82-6.87 (1H, m), 6.95 (1H, dd, J = 2.6, 6.8 Hz), 7.11 (1H, dd, J =9.0, 9.1 Hz), 7.16 (1H, dd, J = 2.6, 9.1 Hz), 7.38 (1H, d, J = 2.6 Hz),7.48 (1H, d, J = 9.1 Hz), 7.86 (1H, d, J = 9.4 Hz), 9.35 (1H, br), 9.48(1H, br). Hydrochloride

TABLE 127

Ex. No. R1 R2 R3 R4 R5 R6 NMR Salt 909 —H —H —F —CH₃ —H

¹H-NMR (DMSO-d₆) δ ppm: 1.58-1.71 (1H, m), 2.08-2.17 (1H, m), 2.17 (3H,d, J = 1.5 Hz), 2.42 (2H, dd, J = 6.9, 8.0 Hz), 2.81-2.89 (1H, m), 2.83(2H, dd, J = 6.9, 8.0 Hz), 3.08-3.14 (2H, m), 3.16- 3.56 (1H, m, withH2O), 4.52-4.61 (1H, m), 6.63-6.69 (1H, m), 6.79 (1H, dd, J = 2.6, 6.9Hz), 6.84-6.86 (3H, m), 7.02 (1H, dd, J = 9.1, 9.1 Hz), 9.17 (1H, br),9.29 (1H, br), 10.07 (1H, s). Hydrochloride 910 —H —H —F —CH₃ —H

¹H-NMR (DMSO-d₆) δ ppm: 1.56-1.69 (1H, m), 2.16-2.65 (1H, m), 2.63 (3H,d, J = 1.5 Hz), 2.78-2.89 (1H, m), 2.83 (2H, dd, J = 6.5, 6.5 Hz), 2.96(3H, s), 3.07-3.19 (2H, m), 3.37-3.45 (2H, m, with H2O), 3.56-3.66 (1H,m), 4.71-4.80 (1H, m), 6.41 (1H, d, J = 2.4 Hz), 6.47 (1H, dd, J = 2.4,8.7 Hz), 7.07-7.12 (1H, m), 7.20 (1H, dd, J = 2.4, 7.0 Hz), 7.29 (1H,dd, J = 8.9, 9.2 Hz), 7.64 (1H, d, J = 8.7 Hz), 9.11 (1H, br), 9.19 (1H,br). Hydrochloride 911 —H —H —F —Cl —H

¹H-NMR (DMSO-d₆) δ ppm: 1.58-1.71 (1H, m), 2.15-2.22 (1H, m), 2.55 (2H,dd, J = 6.4, 8.3 Hz), 2.81-2.89 (1H, m), 2.86 (2H, dd, J = 6.4, 8.3 Hz),3.12-3.17 (2H, m), 3.26 (3H, s), 3.55 (1H, dd, J = 6.9, 11.7 Hz),4.60-4.70 (1H, m), 6.69 (1H, ddd, J = 3.0, 3.9, 9.1 Hz), 6.93 (1H, dd, J= 3.0, 6.3 Hz), 7.03-7.06 (2H, m), 7.15 (1H, d, J = 9.3 Hz), 7.27 (1H,dd, J = 9.1, 9.1 Hz), 9.17 (2H, br). Hydrochloride 912 —H —H —F —Cl —H

¹H-NMR (DMSO-d₆) δ ppm: 1.62-1.72 (1H, m), 2.17-2.27 (1H, m), 2.83-2.94(1H, m), 3.12-3.19 (1H, m), 3.54-3.60 (1H, m), 3.63 (3H, s), 4.67-4.77(1H, m), 6.66 (1H, d, J = 9.5 Hz), 6.74 (1H, ddd, J = 3.1, 3.8, 9.1 Hz),6.99 (1H, dd, J = 3.1, 6.3 Hz), 7.29 (1H, dd, J = 9.1, 9.1 Hz), 7.37(1H, dd, J = 2.6, 8.9 Hz), 7.56- 7.60 (2H, m), 7.88 (1H, d, J = 9.5 Hz),9.13 (1H, br), 9.21 (1H, br). Hydrochloride

TABLE 128

Ex. No. R1 R2 R3 R4 R5 R6 NMR Salt 913 —H —Cl —F —H —H

¹H-NMR (DMSO-d₆) δ ppm; 1.65-1.82 (1H, m), 2.19- 2.40 (1H, m), 2.90-3.10(1H, m), 3.10-3.20 (2H, m), 3.65- 3.80 (1H, m), 4.80-4.90 (1H, m),7.30-7.45 (2H, m), 7.52 (1H, d, J = 2.5 Hz), 7.55-7.69 (2H, m), 7.88(1H, dd, J = 8.4, 5.1 Hz), 8.15 (1H, d, J = 9.4 Hz), 8.83 (1H, d, J =8.4 Hz), 8.94 (1H, d, J = 4.1 Hz), 9.45 (1H, bs), 9.62 (1H, bs)2Hydrochloride 914 —H —H —F —Cl —H

¹H-NMR (DMSO-d₆) δ ppm: 1.56-1.70 (1H, m), 2.12-2.22 (1H, m), 2.46 (2H,dd, J = 7.1, 8.0 Hz), 2.80-2.90 (1H, m), 2.88 (2H, dd, J = 7.1, 8.0 Hz),3.09-3.16 (2H, m), 3.50- 3.60 (1H, m), 4.58-4.68 (1H, m), 6.61 (1H, ddd,J = 3.4, 3.5, 9.1 Hz), 6.86 (1H, dd, J = 2.9, 6.3 Hz), 6.91-7.00 (3H,m), 7.23 (1H, dd, J = 9.1, 9.1 Hz), 8.80 (2 H, br), 10.19 (1H, s).2Trifluoroacetate 915 —H —H —F —H —H

¹H-NMR (DMSO-d₆) δ ppm: 1.59-1.66 (1H, m), 2.10-2.20 (1H, m), 2.43 (2H,dd, J = 7.0, 8.1 Hz), 2.84 (2H, dd, J = 7.0, 8.1 Hz), 2.84-2.92 (1H, m),3.11-3.21 (2H, m), 3.47- 3.55 (1H, m), 4.54-4.64 (1H, m), 6.79-6.89 (5H,m), 7.09 (2H, dd, J = 8.8, 8.9 Hz), 8.71 (2H, br), 10.10 (1H, s).2Trifluoroacetate

TABLE 129

Ex. No. R1 R2 R3 R4 R5 R6 NMR Salt 916 —H —H —F —H —H

¹H-NMR (DMSO-d₆) δ ppm: 1.60-1.71 (1H, m), 2.12-2.22 (1H, m), 2.49-2.54(2H, m, with DMSO-d6), 2.82 (2H, dd, J = 7.4, 8.0), 2.84-2.91 (1H, m),3.12-3.16 (2H, m), 3.23 (3H, s), 3.45-3.55 (1H, m), 4.56-4.65 (1H, m),6.87-6.95 (4H, m), 7.06 (1H, d, J = 9.4 Hz), 7.14 (2H, dd, J = 8.8, 8.9Hz), 8.67 (2H, br). Hydrochloride 917 —H —H —F —H —H

¹H-NMR (DMSO-d₆) δ ppm: 1.58-1.73 (1H, m), 2.10-2.31 (1H, m), 2.41 (2H,dd, J = 7.0, 8.0 Hz), 2.80 (2H, dd, J = 7.0, 8.0 Hz), 2.82-3.14 (1H, m),3.14 (2H, br), 3.46-3.56 (1H, m), 4.54-4.62 (1H, m), 6.31 (1H, d, J =2.2 Hz), 6.47 (1H, dd, J = 2.2, 8.1 Hz), 7.01-7.10 (3H, m), 7.21 (2H,dd, J = 8.7, 8.8 Hz), 8.83 (2H, br), 9.88 (1H, s). Hydrochloride 918 —H—F —CH3 —H —H

¹H-NMR (DMSO-d₆) δ ppm: 1.60-1.70 (1H, m), 2.10 (3H, s), 2.13-2.21 (1H,m), 2.43- 2.48 (2H, m), 2.79-2.90 (1H, m), 2.87 (2H, dd, J = 7.1, 8.0Hz), 3.11 (2H, br), 3.48-3.55 (1H, m), 4.56-4.66 (1H, m), 6.37 (1H, dd,J = 2.4, 8.4 Hz), 6.44 (1H, dd, J = 2.4, 13.0 Hz), 6.90-7.08 (4H, m),9.22 (1H, br), 9.32 (1H, br), 10.19 (1H, s). Hydrochloride

TABLE 130

Ex. No. R1 R2 R3 R4 R5 R6 NMR Salt 919 —H —CH₃ —F —H —H

¹H-NMR (DMSO-d₆) δ ppm: 1.53-1.65 (1H, m), 2.14- 2.21 (1H, m), 2.14 (3H,d, J = 1.6 Hz), 2.44-2.49 (2H, m, with DMSO-d6), 2.63-2.69 (2H, m), 2.85(1H, dd, J = 7.8, 11.6 Hz), 3.13-3.17 (2H, m), 3.28 (3H, s), 3.59 (1H,dd, J = 6.9, 11.6 Hz), 4.57-4.67 (1H, m), 6.33-6.39 (1H, m), 6.51 (1H,dd, J = 3.1, 6.4 Hz), Hydro- chloride 6.91-6.97 (2H, m), 7.15 (1H, d, J= 8.1 Hz), 7.38 (1H, t, J = 8.1 Hz), 9.03 (2H, br). 920 —H —Cl —F —H —H

¹H-NMR (DMSO-d₆) δ ppm: 1.58-1.71 (1H, m), 2.15- 2.25 (1H, m), 2.82-2.92(1H, m), 3.11-3.16 (2H, m), 3.37 (3H, s, with H2O), 3.54-3.60 (1H, m),4.65-4.74 (1H, m), 6.54 (1H, d, J = 9.6 Hz), 6.64-6.69 (1H, m), 6.93(1H, dd, J = 2.9, 6.3 Hz), 7.22-7.30 (2H, m), 7.37 2Hydro- chloride (1H,d, J = 8.7 Hz), 7.53 (1H, d, J = 2.2 Hz), 7.88 (1H, d, J = 9.6 Hz), 9.04(1H, br), 9.13 (1H, br), 11.86 (1H, s).

TABLE 131

Ex. No. R1 R2 R3 R4 R5 R6 NMR Salt 921 —H —H —F —Cl —H

¹H-NMR (DMSO-d₆) δ ppm: 1.18-1.35 (2H, m), 1.66-1.90 (3H, m), 1.95-2.12(1H, m), 2.88-3.46 (7H, m), 3.83 (2H, dd, J = 3.2, 11.1 Hz), 4.18-4.36(1H, brs), 7.11-7.30 (1H, m), 7.30-7.50 (2H, m), Hydro- chloride9.25-9.65 (2H, br). 922 —H —H —F —Cl —H

¹H-NMR (DMSO-d₆) δ ppm: 1.08-1.29 (2H, m), 1.45-1.70 (3H, m), 1.79-2.14(2H, m), 2.85-3.40 (8H, m), 3.73-3.85 (2H, m), 4.28-4.46 (1H, m),6.91-7.08 Hydro- chloride (1H, m), 7.11-7.35 (2H, m), 9.00-9.85 (2H, m).923 —H —H —Cl —CH₃ —H

¹H-NMR (DMSO-d₆) δ ppm: 1.57-1.75 (1H, m), 2.19-2.35 (1H, m), 2.37 (3H,s), 2.83-2.96 (1H, m), 3.00-3.19 (2H, m), 3.58-3.74 (1H, m), 4.80-4.95(1H, m), 7.22 (1H, dd, J = 8.4, 2.4 Hz), 7.40 (1H, 2Hydro- chloride d, J= 2.4 Hz), 7.55-7.66 (2H, m), 7.77 (1H, dd, J = 8.9, 5.3 Hz), 8.17 (1H,J = 2.7 Hz), 8.24 (1H, d, J = 5.3 Hz), 9.62 (2H, br). 924 —H —H —F —Cl—H

¹H-NMR (DMSO-d₆) δ ppm: 1.76-1.93 (6H, m), 2.07-2.09 (1H, m), 2.94 (1H,br), 3.10 (1H, br), 3.13 (2H, s), 3.34- 3.71 (6H, m, with H2O),4.36-4.42 (1H, Hydro- chloride m), 7.02-7.07 (1H, m), 7.24-7.51 (5H, m),7.77 (2H, br), 9.06 (1H, br), 9.40 (1H, br).

TABLE 132

Ex. No. R1 R2 R3 R4 R5 R6 m.p. (° C.) Salt 925 —H —H —F —H —H

195.5-198.5 2Hydrochloride 926 —H —H —Cl —Cl —H

102-105 Hydrochloride 927 —H —H —Cl —Cl —H

119-122 2Hydrochloride 928 —H —H —Cl —Cl —H

123-124 2Hydrochloride 929 —H —H —Cl —Cl —H

191-193 Hydrochloride 930 —H —H —F —Cl —H

150-156 2Hydrochloride 931 —H —F —F —H —H

153-155 Fumarate 932 —H —Cl —H —Cl —H

174.7-176.7 2Hydrochloride 933 —H —H —H —H —H

  227-228.5 2Hydrochloride 934 —H —H —H —H —H

241.5-243.5 2Hydrochloride

TABLE 133

Ex. No. R1 R2 R3 R4 R5 R6 m.p. (° C.) Salt 935 —H —H —F —H —H

133-135 Fumarate 936 —H —Cl —Cl —H —H

134-136 Fumarate 937 —H —F —F —H —H

138-141 Fumarate 938 —H —H —Cl —CH₃ —H

110.3-111.9 Fumarate 939 —H —Cl —H —Cl —H

179.2-181.1 Fumarate 940 —H —H —F —Cl —H

205.5-206   Hydrochloride 941 —H —H —H —H —H

141-144 Fumarate 942 —H —H —H —H —H

135-161 Fumarate 943 —H —H —H —H —H

155-156 Hydrochloride

TABLE 134

Ex. No. R1 R2 R3 R4 R5 R6 m.p. (° C.) Salt 944 —H —H —H —H —H

160-180 Hydrochloride 945 —H —H —F —H —H

155.5-164.5 Hydrochloride 946 —H —H —F —H —H

  161-167.5 Hydrochloride

TABLE 135

Ex. No. R1 R6 NMR Salt 947

¹H-NMR (DMSO-d₆) δ ppm: 1.6-1.8 (1H, m), 2.25-2.4 (1H, m), 2.85-3.0 (1H,m), 3.0-3.2 (2H, m), 3.25- 4.45 (2H, m), 4.9-5.0 (1H, m), 7.45 (1H, dd,J = 1.8, 8.5 Hz), 7.58 (1H, dd, J = 2.3, 8.8 Hz), 7.72 (1H, dd, J = 5.3,8.8 Hz), 7.98 (1H, d, J = 8.5 Hz), 8.08 (1H, s), 8.16 (1H, d, J = 1.6Hz), 8.22 (1H, d, J = 2.8 Hz), 8.25 2Hydrochloride (1H, d, J = 5.0 Hz),9.45 (1H, br), 9.58 (1H, br). 948

¹H-NMR (DMSO-d₆) δ ppm: 1.6-1.8 (1H, m), 2.25-2.4 (1H, m), 2.85-3.25(3H, m), 3.6-3.8 (1H, m), 4.97 (1H, tt, J = 7.7, 7.7 Hz), 7.32 (1H, dd,J = 1.7, 8.6 Hz), 7.65-7.8 (2H, m), 8.16 (1H, s), 8.3-8.4 (3H, m), 9.17(1H, d, J = 0.7 Hz), 9.3-9.8 (2H, m). 2Hydrochloride 949

¹H-NMR (DMSO-d₆) δ ppm: 1.55-1.75 (1H, m), 2.25- 2.4 (1H, m), 2.7-5.3(1H, br), 2.85-3.0 (1H, m), 3.05-3.25 (2H, m), 3.65-3.80 (1H, m), 4.95(1H, tt, J = 7.7, 7.7 Hz), 7.45 (1H, dd, J = 1.9, 8.6 Hz), 7.55-7.6 (1H,m), 7.74 (1H, dd, J = 5.3, 8.8 Hz), 7.81 (1H, d, J = 1.8 Hz), 8.09 (1H,s), 8.19 (1H, d, J = 2.8 Hz), 8.23 2Hydrochloride (1H, d, J = 5.2 Hz),8.33 (1H, d, J = 8.6 Hz), 9.44 (1, br), 9.62 (1H, br). 950

¹H-NMR (DMSO-d₆) δ ppm: 1.55-1.75 (1H, m), 2.2- 2.35 (1H, m), 2.8-3.0(1H, m), 3.0-3.25 (2H, m), 3.55-3.75 (1H, m), 4.35-4.50 (2H, m), 7.20(1H, d, J = 12.2 Hz), 7.28 (1H, dd, J = 1.8, 5.8 Hz), 7.55 (1H, d, J =5.4 Hz), 7.7-7.8 (1H, m), 7.91 (1H, d, J = 5.4 Hz), 2Hydrochloride8.0-8.1 (2H, m), 8.10 (1H, d, J = 2.2 Hz), 9.32 (1H, br), 9.47 (1H, br).951

¹H-NMR (DMSO-d₆) δ ppm: 1.55-1.8 (1H, m), 2.2- 2.35 (1H, m), 2.8-3.0(1H, m), 3.0-3.2 (2H, m), 3.6- 3.75 (1H, m), 4.3-5.0 (2H, m), 7.1-7.25(1H, m), 7.27 (1H, dd, J = 2.0, 8.5 Hz), 7.51 (1H, d, J = 5.5 Hz), 7.76(1H, d, J = 1.1 Hz), 7.87 (1H, d, J = 2Hydrochloride 1.9 Hz), 7.91 (1H,d, J = 5.4 Hz), 8.08 (1H, d, J = 2.2 Hz), 8.20 (1H, d, J = 8.5 Hz), 9.27(1H, br), 9.43 (1H, br). 952

¹H-NMR (DMSO-d₆) δ ppm: 1.6-1.75 (1H, m), 2.2- 2.35 (1H, m), 2.85-3.0(1H, m), 3.0-3.2 (2H, m), 3.6-3.75 (1H, m), 4.32 (1H, br), 4.85 (1H, tt,J = 7.7, 7.7 Hz), 7.19 (1H, ddd, J = 2.4, 2.4 12,0 Hz), 7.37 (1H, dd, J= 1.9, 8.5 Hz), 7.8-7.85 (1H, m), 7.92 (1H, d, J = 8.5 Hz), 8.02 (1H,s), 8.05-8.15 (2H, m), 9.21 2Hydrochloride (1H, br), 9.33 (1H, br).

TABLE 136

Ex. No. R1 R2 R3 R4 R5 R6 m.p. (° C.) Salt 953 —H —H —Cl —Cl —H

96-98 2Hydrochloride 954 —H —H —Cl —Cl —H

126-129 2Hydrochloride 955 —H —H —Cl —Cl —H

139-143 2Hydrochloride 956 —H —H —Cl —Cl —H

117-120 2Hydrochloride 957 —H —H —Cl —Cl —H

155-159 Hydrochloride 958 —H —H —F —Cl —H

101-103 Hydrochloride 959 —H —H —F —Cl —H

157-160 Hydrochloride 960 —H —H —Cl —Cl —H

151-153 2Hydrochloride 961 —H —H —Cl —Cl —H

96-98 Hydrochloride 962 —H —H —F —Cl —H

119-123 2Hydrochloride 963 —H —H —Cl —Cl —H

120-124 2Hydrochloride

TABLE 137

Ex. No. R1 R2 R3 R4 R5 R6 NMR Salt 964 —H —Cl —F —H —H —(CH₂)₂OCH(C₆H₅)₂¹H-NMR (DMSO-d₆) δ ppm; 1.99-2.18 (2H, m), — 3.13-3.34 (2H, m),3.38-3.3.47 (7H, m), 4.23-4.35 (1H, m), 5.25 (1H, s), 6.71-6.78 (1H, m),6.92-7.00 (2H, m), 7.18-7.33 (10H, m) 965 —H —Cl —F —H —H —CH₂CO₂C₂H₅¹H-NMR (DMSO-d₆) δ ppm; 1.15 (3H, t, J = Hydrochloride 7.1 Hz),2.05-2.36 (2H, m), 3.04-3.22 (1H, m), 3.22-3.72 (4H, m), 3.71-4.50 (3H,m), 5.34 (1H, brs), 7.52-7.69 (2H, m), 7.87- 7.98 (1H, m), 9.10-9.70(2H, m). 966 —H —Cl —F —H —H —(CH₂)₂OH ¹H-NMR (DMSO-d₆) δ ppm; 1.25 (1H,s), 1.80- — 1.94 (1H, m), 2.04-2.19 (1H, m), 2.97-3.74 (9H, m),4.05-4.14 (1H, m), 6.76 (1H, ddd, J = 8.9, 3.6, 2.9 Hz), 6.92 (1H, dd, J= 6.2, 2.9 Hz), 7.03 (1H, dd, J = 8.9, 8.8 Hz) 967 —H —Cl —F —H —H—CH₂C(CH₃)₂OH ¹H-NMR (DMSO-d₆) δ ppm; 1.01 (3H, s), Oxalate 1.04 93H,s), 1.88-2.15 (2H, m), 3.03-3.22 (4H, m), 3.22-3.45 (2H, m), 3.45-3.55(5H, m; including 1H, quint at 4.30), 7.01-7.10 (1H, m), 7.23 (1H, t, J= 9.1 Hz), 7.25-7.32 (1H, m). 968 —H —Cl —F —H —H —(CH₂)₂OCH₃ ¹H-NMR(DMSO-d₆) δ ppm; 1.82-2.00 Hydrochloride (1H, m), 2.06-2.20 (1H, m),2.90-3.19 (2H, m), 3.24 (3H, s), 3.26-3.50 (6H, m), 4.44 (1H, quint, J =8.2 Hz), 6.89 (1H, td, J = 3.3, 9.1 Hz), 7.07 (1H, dd, J = 3.3, 9.1 Hz),7.25 (1H, t, J = 9.1Hz), 9.z), 9.34 (1H, br), 9.52 (1H, br). 969 —H —Cl—F —H —H —CH₂CO₂H ¹H-NMR (DMSO-d₆) δ ppm; 2.05-2.34 (2H, Hydrochloridem), 2.80-4.40 (5H, m), 5.22 (1H, brs), 7.51- 7.71 (2H, m), 7.89 (1H, dd,J = 1.8, 5.3 Hz), 7.15-7.65 (2H, br), 9.85-11.65 (2H, br). 970 —H —Cl —F—H —H —CH₂CONH₂ 971 —H —Cl —F —H —H —CH₂CONHCH₃ ¹H-NMR (DMSO-d₆) δ ppm;2.09-2.31 (2H, Hydrochloride m), 2.63 (3H, d, J 4.6 Hz), 3.05-3.25 (1H,m), 3.25-3.54 (3H, m), 3.54-3.79 (1H, m), 5.27 (1H, brs), 7.50-7.70 (2H,m), 7.80- 7.97 (1H, m), 8.92 (1H, brs), 9.36-9.85 (2H, m), 9.80-11.10(1H, br).

TABLE 138

Ex. No. R1 R2 R3 R4 R5 R6 NMR Salt 972 —H —Cl —F —H —H —CH₂CON(CH₃)₂¹H-NMR (DMSO-d₆) δ ppm; 2.07-2.40 (2H, Hydrochloride m), 2.89 (3H, s),2.90 (3H, s), 3.02-3.24 (1H, m), 3.24-3.83 (4H, m), 5.63 (1H, brs),7.53-7.69 (2H, m), 7.83-7.93 (1H, m), 9.32- 9.75 (2H, m), 9.82-10.50(1H, m). 973 —H —Cl —F —H —H —CH₂CH═CH₂ ¹H-NMR (DMSO-d₆) δ ppm;1.76-1.95 (1H, Hydrochloride m), 2.10-2.25 (1H, m), 2.85-3.02 (1H, m),3.02-3.19 (1H, m), 3.25-3.50 (2H, m), 3.89 (2H, brs), 4.59 (1H, quint, J= 7.8 Hz), 5.05-5.20 (2H, m), 5.76-5.94 (1H, m), 6.69- 6.82 (1H, m),6.88-6.97 (1H, m), 7.23 (1H, t, J = 9.2 Hz), 8.90-9.95 (2H, br). 974 —H—Cl —F —H —H —(CH₂)₃OH ¹H-NMR (DMSO-d₆) δ ppm; 1.49-2.79 (2H,Hydrochloride m), 1.81-2.04 (2H, m), 2.05-2.20 (1H, m), 2.82-3.20 (2H,m), 3.20-3.50 (6H, m), 4.33- 4.52 (1H, m), 6.84-7.04 (1H, m), 7.04-7.21(1H, m), 7.22-7.35 (1H, m), 9.15-9.75 (2H, m). 975 —H —Cl —F —H —H—(CH₂)₂C(CH₃)₂OH 976 —H —Cl —F —H —H —(CH₂)₃OCH₃ ¹H-NMR (DMSO-d₆) δ ppm;1.55-1.72 (2H, Oxalate m), 1.80-1.99 (1H, m), 2.04-2.20 (1H, m), 2.93(1H, dd, J = 9.4, 11.6 Hz), 3.05-3.50 (10H, m), 4.40 (1H, quint, J= 7.9Hz), 5.25-8.20 (6H, m; including 6.80-6.90 (1H, m), 7.00-7.10 (1H, m),and 7.26 (1H, t, J = 9.1 Hz).

TABLE 139

Ex. No. R1 R2 R3 R4 R5 R6 NMR Salt 977 —H —Cl —F —H —H

¹H-NMR (CDCl₃) δ ppm; 1.58-1.71 (1H, m), 2.03-2.18 (2H, m), 2.79 (1H,dd, J = 11.2, 4.3 Hz), 2.91 (1H, ddd, J = 11.2, 8,2 6.2 Hz), 3.03-3.15(2H, m), 4.25-4.35 (1H, m), 6.88- 6.92 (1H, m), 6.97-7.15 (3H, m), 7.25(1H, dd, J = 8.7, 8.7 Hz), 7.49 (1H, ddd, J = 8.7, 4.2, — 2.6 Hz), 7.66(1H, dd, J = 6.5, 2.6 Hz) 978 —H —Cl —F —H —H

¹H-NMR (CDCl₃) δ ppm; 1.59 (1H, s), 1.66-1.81 (1H, m), 2.00-2.16 (1H,m), 2.83-2.93 (3H, m), 3.12 (1H, dd, J = 11.5, 6.6 Hz), 3.22 (1H, t, J =8.7 Hz), 4.20-4.31 (1H, m), 4.62 (1H, t, J = 8.7 Hz), 6.44 (1H, ddd, J =9.1, 3.6, 3.0 Hz), 6.62 — (1H, dd, J = 6.2, 3.0 Hz), 6.75-6.85 (2H, m),6.86-6.94 (2H, m) 979 —H —Cl —F —H —H

980 —H —Cl —F —H —H

¹H-NMR (CDCl₃) δ ppm; 1.64-1.84 (2H, m), 2.07-2.19 (1H, m), 2.87-3.02(3H, m), 3.21 (1H, dd, J = 11.5, 6.7 Hz), 4.34-4.44 (1H, m), 6.81 (1H,ddd, J = 8.9, 4.1, 2.8 Hz), 6.90-6.95 (2H, m), 7.00 (1H, dd, J = 6.5,2.8 Hz), 7.07 (1H, dd, J = 8.9, 8.7 Hz), 7.30-7.34 (1H, m), 7.39-7.45(2H, m), 7.49-7.61 (4H, m) Oxalate 981 —H —Cl —F —H —H

¹H-NMR (CDCl₃) δ ppm; 1.66-1.82 (1H, m), 1.98-2.12 (1H, m), 2.83-3.20(5H, m), 3.40- 3.52 (4H, m), 4.02-4.15 (1H, m), 5.23 (1H, s), 6.67 (1H,ddd, J = 8.9, 3.6, 3.0 Hz), 6.89 (1H, dd, J = 6.2, 3.0 Hz), 6.96 (1H,dd, J = 8.9, 8.8 Hz), 7.16-7.21 (4H, m), 7.25-7.32 (4H, m), — 982 —H —Cl—F —H —H

¹H-NMR (CDCl₃) δ ppm; 1.67-1.82 (1H, m), 1.98-2.13 (1H, m), 2.83-3.20(4H, m), 3.24 (1H, br), 3.40-3.52 (4H, m), 4.03-4.15 (1H, m), 5.26 (1H,s), 6.67 (1H, ddd, J = 9.0, 3.6, 3.0 Hz), 6.89 (1H, dd, J = 6.2, 3.0Hz), 6.91-7.05 (5H, m), 7.20-7.29 (4H, m) —

TABLE 140

Ex. No. R1 R2 R3 R4 R5 R6 NMR Salt 983 —H —Cl —F —H —H

¹H-NMR (CDCl₃) δ ppm; 1.68-1.82 (2H, m), 2.03-2.17 (1H, m), 2.83-2.95(3H, m), 3.16 (1H, dd, J = 11.6, 6.7 Hz), 4.25-4.35 (1H, m), 6.58 (1H,ddd, J = 9.0, 3.9, 2.9 Hz), 6.78 (1H, dd, J = 6.3, 2.9 Hz), 6.94-7.06(7H, m), 7.09- Oxalate 7.16 (1H, m), 7.32-7.40 (2H, m) 984 —H —Cl —F —H—H

¹H-NMR (CDCl₃) δ ppm; 1.67-1.90 (2H, m), 2.04-2.18 (1H, m), 2.80-3.01(3H, m), 3.05- 3.30 (1H, m), 4.20-4.44 (1H, m), 6.58-6.69 (1H, m),6.78-6.82 (1H, m), 6.84-7.00 (7H, m), 7.27-7.34 (2H, m) — 985 —H —Cl —F—H —H

¹H-NMR (CDCl₃) δ ppm; 1.66-1.80 (2H, m), 2.02-2.17 (1H, m), 2.80-2.95(3H, m), 3.03- 3.26 (1H, m), 4.24-4.37 (1H, m), 6.54-6.62 (1H, m),6.74-6.81 (1H, m), 6.83-7.10 (9H, m) —

TABLE 141

Ex. No. R1 R2 R3 R4 R5 R6 NMR Salt 986 —H —Cl —F —H —H

¹H-NMR (CDCl₃) δ ppm; 1.70-1.84 (2H, m), 2.06-2.20 (1H, m), 2.86-2.98(3H, m), 3.18-3.26 (1H, m), 4.33-4.45 (1H, m), 6.78-6.85 (1H, m),6.87-6.94 (2H, m), 6.98-7.02 (1H, m), 7.04-7.16 (3H, m), 7.43-7.55 (4H,m) — 987 —H —Cl —F —H —H

¹H-NMR (CDCl₃) δ ppm; 1.68 (1H, s), 1.69-1.83 (1H, m), 2.04-2.20 (1H,m), 2.75-2.97 (3H, m), 3.22 (1H, dd, J = 11.5, 6.8 Hz), 4.34-4.45 (1H,m), 6.84 (1H, ddd, J = 8.8, 4.1, 2.7 Hz), 6.85- 6.92 (2H, m), 7.03 (1H,dd, J = 6.5, 2.7 Hz), 7.10 (1H, dd, J = 8.8, 8.7 Hz), 7.34-7.41 (2H, m),7.43-7.52 (4H, m) — 988 —H —Cl —F —H —H

2Trifluoroacetate 989 —H —Cl —F —H —H

¹H-NMR (CDCl₃) δ ppm; 1.85-2.1 (1H, m), 2.15-2.35 (1H, m), 2.35-2.95(1H, m), 3.14 (1H, br), 3.33 (2H, br), 3.59 (1H, br), 4.55-4.8 (1H, m),6.8- 6.95 (1H, m), 7.01 (1H, dd, J = 2.7, 2Trifluoroacetate 6.3 Hz),7.05-7.2 (2H, m), 7.55 (1H, d, J = 2.0 Hz), 8.06 (1H, d, J = 8.8 Hz),8.97 (1H, s), 9.86 (2H, br). 990 —H —Cl —F —H —H

¹H-NMR (DMSO-d₆) δ ppm; 1.6-1.8 (1H, m), 2.15-2.3 (1H, m), 2.85-3.0 (1H,m), 3.05-3.25 (2H, m), 3.55-3.7 (1H, m), 4.03 (3H, s), 4.76 (1H, tt, J =7.2, 7.2 Hz), 5.28 (1H, br), 6.8-6.9 (1H, br), 6.8-6.9 (1H, m), 7.08(1H, dd, J = 2.9, 6.4 Hz), 7.32 (1H, dd, J = 2Hydrochloride 9.0, 9.0Hz), 7.44 (1H, s), 7.71 (1H, d, J = 8.6 Hz), 8.01 (1H, s), 9.36 (1H,br), 9.52 (1H, br).

TABLE 142

Ex. No. R1 R2 R3 R4 R5 R6 NMR Salt 991 —H —Cl —F —H —H

¹H-NMR (DMSO-d₆) δ ppm; 1.5-1.75 (1H, m), 2.1-2.3 (1H, m), 2.75-2.95(1H, m), 2.95-3.25 (2H, m), 3.45-3.65 (1H, m), 3.65-4.35 (4H, m), 4.72(1H, tt, J = 7.2, 7.2 Hz), 6.59 (1H, ddd, J = 3.5, 3.5, 9.1 Hz), -6.79(1H, dd, J = 3.0, 6.3 Hz), 7.1-7.25 (2H, m), 7.67 (1H, d, J =Hydrochloride 1.5 Hz), 7.75 (1H, d, J = 8.8 Hz), 8.08 (1H, d, J = 0.4Hz), 9.31 (1H, br), 9.42 (1H, br). 992 —H —Cl —F —H —H

993 —H —Cl —F —H —H

994 —H —Cl —F —H —H

¹H-NMR (CDCl₃) δ ppm; 1.85-2.05 (1H, m), 2.2-2.35 (1H, m), 3.1-3.25 (1H,m), 3.25-3.4 (2H, m), 3.55-3.7 (1H, m), 4.79 (1H, tt, J = 6.8, 6.8 Hz),6.60 (1H, ddd, J = 3.4, 3.4, 9.0 Hz), 6.76 (1H, dd, J = 3.0, 6.0 Hz),5.95 (1H, dd, J = 8.8, 8.8 Hz), 2Trifluoroacetate 7.25-7.45 (4H, m),7.85 (1H, dd, J = 1.2, 7.6 Hz), 9.07 (1H, br), 9.24 (1H, br), 10.44 (1H,br). 995 —H —Cl —F —H —H

¹H-NMR (CDCl₃) δ ppm; 1.8-2.05 (4H, m), 2.15-2.35 (1H, m), 3.0-3.2 (1H,m), 3.25-3.45 (2H, m), 3.5-3.7 (1H, m), 4.64 (1H, tt, J = 6.8, 6.8 Hz),6.46 (1H, ddd, J = 3.4, 3.4, 9.1 Hz), 6.60 (1H, dd, J = 3.0, 6.1 Hz),6.96 (1H, dd, J = 8.8, 8.8 Hz), 2Trifluoroacetate 7.05-7.15 (2H, m),8.85-9.65 (2H, m), 10.42 (1H, br).

TABLE 143

Ex. No. R1 R2 R3 R4 R5 R6 NMR Salt 996 —H —Cl —F —H —H

997 —H —Cl —F —H —H

¹H-NMR (CDCl₃) δ ppm; 2.05-2.2 (1H, m), 2.2-2.35 (1H, m), 2.44 (3H, d, J= 1.0 Hz), 3.15-3.45 (3H, m), 3.5-3.7 (1H, m), 4.59 (1H, tt, J = 6.6,6.6 Hz), 6.55-6.65 (2H, 2Trifluoroacetate m), 6.69 (1H, ddd, J = 3.4,9.0 Hz), 6.84 (1H, dd, J = 3.0, 6.1 Hz), 7.00 (1H, dd, J = 8.7, 8.7 Hz),9.14 (2H, br), 9.52 (1H, br). 998 —H —Cl —F —H —H

¹H-NMR (DMSO-d₆) δ ppm; 1.6-1.75 (1H, m), 2.05-2.2 (1H, m), 2.39 (3H, d,J = 0.7 Hz), 2.86 (1H, dd, J = 7.4, 11.5 Hz), 2.95-3.15 (2H, m), 3.50(1H, dd, J = 7.0, Fumarate 11.5 Hz), 3.65-6.1 (4H, m), 6.46 (2H, s),6.50 (1H, s), 6.7-6.85 (1H, m), 6.9-7.0 (2H, m), 7.27 (1H, dd, J = 9.1,9.1 Hz). 999 —H —Cl —F —H —H

2Trifluoroacetate

TABLE 144

Ex. No. R1 R6 NMR Salt 1000

¹H-NMR (DMSO-d₆) δ ppm; 1.7-1.85 (1H, m), 2.15-2.3 (1H, m), 2.9-3.2 (3H,m), 3.53 (1H, dd, J = 7.0, 11.5 Hz), 4.73 (1H, tt, J = 7.3, 7.3 Hz),6.47 (2H, s), 6.82 (1H, dd, J = 1.4, 5.1 Hz), 6.95 (1H, dd, J = 2.4, 9.0Hz), 7.26 (1H, dd, J = 1.4, 3.1 Hz), 7.25-7.35 (2H, m), 7.35-7.45 (1H,m), 7.59 (1H, dd, Fumarate J = 3.1, 5.1 Hz), 7.7-7.8 (3H, m), 10.3 (3H,br). 1001

¹H-NMR (DMSO-d₆) δ ppm; 1.6-1.9 (1H, m), 2.0-2.35 (1H, m), 2.66-5.55(8H, m), 6.48 (2H, s), 6.68 (1H, dd, J = 1.4, 5.1 Hz), 6.92 (1H, dd, J =2.1, 8.6 Hz), 7.04 (1H, dd, J = 1.4, 3.0 Hz), 7.35 (1H, d, J = 5.5 Hz),7.50 (1H, dd, J = 3.1, 5.1 Hz), 7.55-7.65 (2H, m), 7.75 (1H, d, J = 8.6Hz). Fumarate 1002

¹H-NMR (DMSO-d₆) δ ppm; 1.55-1.9 (1H, m), 2.0-2.25 (1H, m), 2.3-5.45(8H, m), 6.48 (2H, s), 6.59 (1H, dd, J = 1.4, 5.1 Hz), 6.92 (1H, dd, J =1.4, 3.0 Hz), 6.99 (1H, dd, J = 2.2, 8.7 Hz), 7.38 (1H, d, J = 5.4 Hz),7.45 (1H, dd, J = 3.1, 5.1 Hz), 7.54 (1H, d, J = 2.1 Hz), 7.75 (1H, d, J= 5.4 Hz), 7.91 Fumarate (1H, d, J = 8.6 Hz).

TABLE 145

Ex. No. R1 R2 R3 R4 R5 R6 MS(M + 1) 1003 —H —Cl —F —H —H —(CH₂)₂CO₂CH₃1004 —H —Cl —F —H —H —(CH₂)₂CO₂C₂H₅ 1005 —H —Cl —F —H —H—(CH₂)₂CO₂CH₂C₆H₅ 1006 —H —Cl —F —H —H —(CH₂)₂CON(CH₃)₂ 314 1007 —H —Cl—F —H —H —(CH₂)₂COCH₃ 1008 —H —Cl —F —H —H —(CH₂)₂COC₂H₅ 1009 —H —Cl —F—H —H —(CH₂)₂COC₆H₅ 1010 —H —Cl —F —H —H —(CH₂)₂CH(OH)CH₃ 1011 —H —Cl —F—H —H —(CH₂)₂CH(OH)C₂H₅ 1012 —H —Cl —F —H —H —(CH₂)₂CH(OH)C₆H₅ 1013 —H—Cl —F —H —H —(CH₂)₂CH(OH)(CH₃)₂ 1014 —H —Cl —F —H —H —(CH₂)₃SC₆H₅ 3651015 —H —Cl —F —H —H —(CH₂)₃S(CH₂)₂N(C₂H₅)₂ 1016 —H —Cl —F —H —H—(CH₂)₃S(CH₂)₂CH₃ 331 1017 —H —Cl —F —H —H —(CH₂)₃SCH₂C₆H₅ 379 1018 —H—Cl —F —H —H —(CH₂)₃S(CH₂)₂C₆H₅ 393 1019 —H —Cl —F —H —H—(CH₂)₃S(CH₂)₂NH₂ 1020 —H —Cl —F —H —H —(CH₂)₃SC₂H₅ 1021 —H —Cl —F —H —H—(CH₂)₃S(CH₂)₂OH 333 1022 —H —Cl —F —H —H —(CH₂)₃S(CH₂)₂CO₂CH₃ 375 1023—H —Cl —F —H —H —(CH₂)₃SCH₂CO₂CH₃ 361 1024 —H —Cl —F —H —H—(CH₂)₃S-cyclo-C₅H₉ 357 1025 —H —Cl —F —H —H —(CH₂)₃S-cyclo-C₆H₁₁ 3711026 —H —Cl —F —H —H —(CH₂)₃S(CH₂)₃C₆H₅ 407 1027 —H —Cl —F —H —H—(CH₂)₃S(CH₂)₂OC₆H₅ 409

Table 146

Ex. No. R1 R2 R3 R4 R5 R6 MS(M + 1) 1028 —H —Cl —F —H —H

1029 —H —Cl —F —H —H

380 1030 —H —Cl —F —H —H

379 1031 —H —Cl —F —H —H

399 1032 —H —Cl —F —H —H

1033 —H —Cl —F —H —H

1034 —H —Cl —F —H —H

422 1035 —H —Cl —F —H —H

1036 —H —Cl —F —H —H

1037 —H —Cl —F —H —H

395

TABLE 147

Ex. No. R1 R2 R3 R4 R5 R6 MS(M + 1) 1038 —H —Cl —F —H —H

1039 —H —Cl —F —H —H

366 1040 —H —Cl —F —H —H

366 1041 —H —Cl —F —H —H

395 1042 —H —Cl —F —H —H

367 1043 —H —Cl —F —H —H

387 1044 —H —Cl —F —H —H

369 1045 —H —Cl —F —H —H

405 1046 —H —Cl —F —H —H

422 1047 —H —Cl —F —H —H

433

TABLE 148

Ex. No. R1 R2 R3 R4 R5 R6 MS(M + 1) 1048 —H —Cl —F —H —H

406 1049 —H —Cl —F —H —H

1050 —H —Cl —F —H —H

369 1051 —H —Cl —F —H —H

1052 —H —Cl —F —H —H

369 1053 —H —Cl —F —H —H

1054 —H —Cl —F —H —H

386 1055 —H —Cl —F —H —H

1056 —H —Cl —F —H —H

371 1057 —H —Cl —F —H —H

409

TABLE 149

Ex. No. R1 R2 R3 R4 R5 R6 MS(M + 1) 1058 —H —Cl —F —H —H

413 1059 —H —Cl —F —H —H

393 1060 —H —Cl —F —H —H

1061 —H —Cl —F —H —H

TABLE 150

Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 MS(M + 1) 1062 —H —H —CF₃ —H —H —H —H—F —H 326 1063 —H —H —N(CH₃)₂ —H —H —H —H —F —H 301 1064 —H —OCH₃ —H —H—H —H —H —F —H 288 1065 —H —OC₂H₅ —H —H —H —H —H —F —H 302 1066 —H —SCH₃—H —H —H —H —H —F —H 304 1067 —H —CF₃ —Cl —H —H —H —H —F —H 360 1068 —H—H —CH₃ —H —H —H —H —F —H 272 1069 —Cl —Cl —H —H —H —H —H —F —H 1070 —H—H —SCH₃ —H —H —H —H —F —H 304 1071 —H —H —CH(CH₃)₂ —H —H —H —H —F —H300 1072 —H —H —OC₆H₅ —H —H —H —H —F —H 350 1073 —H —H —C₂H₅ —H —H —H —H—F —H 286 1074 —H —CF₃ —F —H —H —H —H —F —H 344 1075 —F —CF₃ —H —H —H —H—H —F —H 1076 —Cl —H —H —H —H —H —H —F —H 292 1077 —H —H —OCH —H —H —H—H —F —H 288 1078 —CH₃ —CH₃ —H —H —H —H —H —F —H 286 1079 —C₂H₅ —H —H —H—H —H —H —F —H 286 1080 —H —Cl —Cl —H —H —H —H —F —H 326 1081 —H —F —F—H —H —H —H —F —H 294 1082 —H —F —H —F —H —H —H —F —H 294 1083 —H —H—CF₃ —F —H —H —H —F —H 344 1084 —CF₃ —F —H —H —H —H —H —F —H 1085 —F —H—CF₃ —H —H —H —H —F —H 344 1086 —H —CF₃ —H —F —H —H —H —F —H 344 1087 —H—CF₃ —CH₃ —H —H —H —H —F —H 340 1088 —H —CF₃ —OCH₃ —H —H —H —H —F —H 3561089 —H —CH₃ —N(CH₃)₂ —CH₃ —H —H —H —F —H 329 1090 —H —CH(CH₃)₂ —H —H —H—H —H —F —H 300 1091 —H —F —Br —H —H —H —H —F —H 1092 —H —F —H —Cl —H —H—H —F —H 310 1093 —H —CH₃ —OCH₃ —CH₃ —H —H —H —F —H 316 1094 —H —CH₃ —H—CH₃ —H —H —H —F —H 286

TABLE 151

Ex. No. R1 R2 R3 R4 R5 R6 R7 R8 R9 MS(M + 1) 1095 —H —F —CH₃ —H —H —H —H—F —H 290 1096 —H —F —Cl —H —H —H —H —F —H 310 1097 —H —F —F —H —F —H —H—F —H 1098 —F —H —F —H —H —H —H —F —H 1099 —H —F —H —H —F —H —H —F —H294 1100 —H —F —H —H —H —H —H —F —H 276 1101 —H —Cl —CH₃ —H —H —H —H —F—H 306 1102 —H —F —F —F —H —H —H —F —H 312 1103 —F —F —H —H —H —H —H —F—H 294 1104 —H —F —OCH₃ —H —H —H —H —F —H 306 1105 —H —CH₃ —Cl —H —H —H—H —F —H 306 1106 —H —H —C₃H₇ —H —H —H —H —F —H 300 1107 —H —C₂H₅ —H —H—H —H —H —F —H 1108 —H —OCH₃ —OCH₃ —H —H —H —H —F —H 318 1109 —H —Cl —H—H —H —H —H —F —H 292 1110 —H —CH₃ —CH₃ —H —H —H —H —F —H 286 1111 —H—CH₃ —OCH₃ —H —H —H —H —F —H 302 1112 —H —CH₃ —F —CH₃ —H —H —H —F —H 3041113 —H —H —Cl —H —H —H —H —F —H 292 1114 —H —H —H —H —H —H —H —F —H 2581115 —H —H —F —H —H —H —H —F —H 276 1116 —H —H

—H —H —H —H —F —H 341 1117 —H —H

—H —H —H —H —F —H 325 1118 —H

—H —H —H —H —H —F —H

TABLE 152

Ex. No. R1 R6 MS(M + 1) 1119

293 1120

259 1121

260 1122

309 1123

309 1124

1125

260 1126

323 1127

309 1128

TABLE 153

Ex. MS No. R1 R6 (M + 1) 1129

314 1130

309 1131

310 1132

288 1133

1134

1135

320 1136

264 1137

265 1138

TABLE 154

Ex. MS No. R1 R6 (M + 1) 1139

1140

288 1141

323 1142

377 1143

315 1144

323 1145

1146

339 1147

377 1148

TABLE 155

MS Ex. No. R1 R6 (M + 1) 1149

1150

314 1151

316 1152

308 1153

329 1154

308 1155

302 1156

330 1157

309 1158

310

TABLE 156

Ex. No. R1 R6 MS(M + 1) 1159

329 1160

302 1161

300 1162

323 1163

338 1164

341 1165

326 1166

346 1167

314 1168

298

TABLE 157

Ex. MS No. R1 R6 (M + 1) 1169

315 1170

339 1171

353 1172

1173

298

TABLE 158

Ex. No. R1 R2 R3 R4 R5 R6 MS(M + 1) 1174 —H —Cl —F —H —H

344 1175 —H —Cl —F —H —H

332 1176 —H —Cl —F —H —H

340

TABLE 159

Ex. No. R1 R2 R3 R4 R5 R6 NMR salt 1177 —H —H —F —Cl —H

¹H-NMR (DMSO-d₆) δppm: 1.55-1.75 (1H, m), 2.1-2.25 (1H, m), 2.8-2.95(1H, m), 3.0-3.25 (2H, m), 3.5-3.65 (1H, m), 4.19 (3H, s), 4.64 (1H, tt,J = 7.3, 7.3 Hz), 5.01 (1H, br), 6.60 (1H, ddd, J = 3.5, 3.5, 9.1 Hz),6.81 (1H, dd, J = 3.0, 6.3 Hz), 6.96 (1H, dd, J = 2.0, 9.0 Hz), 7.22(1H, dd, J = 9.1, 9.1 Hz), 7.61 (1H, d, J = 1.5 Hz), 7.68 (1H, d, J =9.0 Hz), 8.39 (1H, s), 9.28 (1H, br), 9.39 (1H, br). 2Hydrochloride 1178—H —H —F —Cl —H

¹H-NMR (DMSO-d₆) δppm: 1.6-1.75 (1H, m), 2.1-2.3 (1H, m), 2.8-3.0 (1H,m), 3.05-3.25 (2H, m), 3.5-3.65 (1H, m), 4.18 (3H, s), 4.72 (1H, tt, J =7.3, 7.3 Hz), 5.88 (1H, br), 6.67 (1H, dd, J = 1.9, 8.9 Hz), 6.8-6.9(1H, m), 7.07 (1H, dd, J = 2.9, 6.4 Hz), 7.25-7.4 (2H, m), 7.73 (1H, dd,J = 0.3, 8.9 Hz), 8.42 (1H, s), 9.43 (1H, br), 9.56 (1H, br).2Hydrochloride 1179 —H —H —H —H —H

¹H-NMR (DMSO-d₆) δppm: 1.6-1.8 (1H, m), 2.1-2.25 (1H, m), 2.8-2.95 (1H,m), 3.0-3.25 (2H, m), 3.5-3.65 (1H, m), 4.0- 4.5 (4H, m), 4.70 (1H, tt,J = 7.3, 7.3 Hz), 6.70 (2H, d, J = 7.9 Hz), 6.80 (1H, dd, J = 7.3, 7.3Hz), 6.92 (1H, dd, J = 2.0, 9.0 Hz), 7.1-7.25 (2H, m), 7.55 (1H, d, J =1.4 Hz), 7.64 (1H, d, J = 9.0 Hz), 8.36 (1H, s), 9.30 (1H, br), 9.47(1H, br). 2Hydrochloride 1180 —H —H —H —H —H

¹H-NMR (DMSO-d₆) δppm: 1.6-1.8 (1H, m), 2.1-2.25 (1H, m), 2.8-3.0 (1H,m), 3.0-3.25 (2H, m), 3.5-3.65 (1H, m), 4.15 (3H, s), 4.22 (1H, br),4.73 (1H, tt, J = 7.3, 7.3 Hz), 6.60 (1H, dd, J = 1.8, 8.9 Hz), 6.91(2H, d, J = 7.6 Hz), 7.02 (1H, dd, J = 7.3, 7.3 Hz), 7.22 (1H, s),7.25-7.4 (2H, m), 7.66 (1H, d, J = 8.9 Hz), 8.37 (1H, s), 9.26 (1H, br),9.42 (1H, br). 2Hydrochloride

Pharmacological Test 1

Evaluation of Inhibitory Activity of Test Compound on Serotonin (5-HT)Uptake into Rat Brain Synaptosome

Male Wistar rats were decapitated and the brains were removed and thefrontal cortices were dissected. The separated frontal cortices werehomogenized in 20 volumes as weight of 0.32 M sucrose solution by aPotter-type homogenizer. The homogenate was centrifuged at 1000 g at 4°C. for 10 minutes, and the supernatant was then centrifuged at 20000 gat 4° C. for 20 minutes. The pellet was resuspended in incubation buffer(20 mM HEPES buffer (pH 7.4)) containing 10 mM glucose, 145 mM sodiumchloride, 4.5 mM potassium chloride, 1.2 mM magnesium chloride, and 1.5mM calcium chloride) and used as crude synaptosome fractions.

The uptake reaction mixture was suspended in a final volume of 200 μlcontaining pargyline (final concentration of 10 μM) and sodium ascorbate(final concentration of 0.2 mg/ml) in each well of96-well-round-bottom-plate.

Solvent, unlabeled 5-HT, and serial diluted test compounds were added ineach well, and synaptosome fraction of 1/10 volume of the final volumewere added. After a 10 min preincubation at 37° C., the uptake wasinitiated by the addition of tritium-labeled 5-HT solution (finalconcentration of 8 nM) at 37° C. The uptake was stopped after 10 minutesby filtration under vacuum through a 96-well glass fiber filter plate.After washing the filter with cold physiological saline and drying up,Microscint-O (Perkin-Elmer) was added, and remained radioactivity on thefilter was measured.

The total uptake activity with only solvent was determined as 100%, andthe nonspecific uptake activity with unlabeled 5-HT (final concentrationof 10 μM) was determined as 0%. The 50% inhibitory concentrations werecalculated based on the concentrations of the test compounds and theirinhibitory activities. Table 160 shows the results.

TABLE 160 Test Compound 50% inhibittory concentration (nM) Compound ofExample 5 1.6 Compound of Example 7 3.0 Compound of Example 19 0.7Compound of Example 40 0.8 Compound of Example 73 0.6 Compound ofExample 90 1.2 Compound of Example 114 0.8 Compound of Example 131 0.6Compound of Example 145 0.6 Compound of Example 149 1.2 Compound ofExample 151 0.8 Compound of Example 154 0.8 Compound of Example 268 0.8Compound of Example 278 2.2 Compound of Example 306 1.4 Compound ofExample 894 2.6 Compound of Example 895 3.0 Compound of Example 896 2.5Compound of Example 899 0.7 Compound of Example 900 1.5 Compound ofExample 901 0.7 Compound of Example 903 1.2 Compound of Example 912 1.0Compound of Example 913 0.8 Compound of Example 917 0.7 Compound ofExample 930 0.8 Compound of Example 934 1.8 Compound of Example 961 2.8Compound of Example 963 1.0 Compound of Example 967 0.9 Compound ofExample 989 0.6

Pharmacological Test 2

Evaluation of Inhibitory Activity of Test Compound on Norepinephrine(NE) Uptake into Rat Brain Synaptosome

Male Wistar rats were decapitated and the brains were removed and thehippocampi were dissected. The separated hippocampi were homogenaized in20 volumes as weight of 0.32 M sucrose solution by a Potter-typehomogenizer. The homogenate was centrifuged at 1000 g at 4° C. for 10minutes, and the supernatant was then centrifuged at 20000 g at 4° C.for 20 minutes. The pellet was resuspended in incubation buffer (20 mMHEPES buffer (pH 7.4)) containing 10 mM glucose, 145 mM sodium chloride,4.5 mM potassium chloride, 1.2 mM magnesium chloride, and 1.5 mM calciumchloride) and used as crude synaptosome fraction.

The uptake reaction mixture was suspended in final volume of 200 μlcontaining pargyline (final concentration of 10 μM) and sodium ascorbate(final concentration of 0.2 mg/ml) in each well of96-well-round-bottom-plate.

Solvent, unlabeled NE, and serial diluted test compounds were added toeach well, and synaptosome fraction of 1/10 volume of the final volumewere added. After 10 minutes preincubation at 37° C., the uptake wasinitiated by the addition of tritium-labeled NE solution (finalconcentration of 12 nM) at 37° C. The uptake was stopped after 10minutes by filtration under vacuum through a 96-well glass fiber filterplate. After washing the filter with coldphysiological saline and dryingup, Microscint-0 (Perkin-Elmer) was added, and remained radioactivity onthe filter was measured.

The total uptake activity with only solvent was determined as 100%, andthe nonspecific uptake activity with unlabeled NE (final concentrationof 10 μM) was determined as 0%. The 50% inhibitory concentrations werecalculated based on the concentrations of the test compounds and theirinhibitory activities. Table 161 shows the results.

TABLE 161 Test Compound 50% inhibitory concentration (nM) Compound ofExample 1 0.6 Compound of Example 7 0.4 Compound of Example 20 0.8Compound of Example 22 2.2 Compound of Example 44 0.4 Compound ofExample 90 0.7 Compound of Example 98 0.3 Compound of Example 114 0.4Compound of Example 116 0.1 Compound of Example 131 0.2 Compound ofExample 154 0.2 Compound of Example 188 0.1 Compound of Example 223 0.2Compound of Example 242 0.2 Compound of Example 244 0.5 Compound ofExample 256 0.1 Compound of Example 278 0.3 Compound of Example 289 0.1Compound of Example 306 0.8 Compound of Example 894 0.3 Compound ofExample 895 0.5 Compound of Example 896 0.9 Compound of Example 900 0.6Compound of Example 903 0.7 Compound of Example 913 0.8 Compound ofExample 922 0.5 Compound of Example 930 1.0 Compound of Example 951 0.5Compound of Example 961 0.7 Compound of Example 963 0.8 Compound ofExample 967 0.1 Compound of Example 989 0.3 Compound of Example 990 0.8Compound of Example 1000 0.4 Compound of Example 1001 0.1 Compound ofExample 1002 0.1

Pharmacological Test 3

Evaluation of Inhibitory Activity of Test Compound on Dopamine (DA) intoRat Brain Synaptosome

Male Wistar rats were decapitated and the brains were removed and thestriata were dissected. The separated striata were homogenized in 20volumes as weight of 0.32 M sucrose solution by a Potter-typehomogenizer. The homogenate was centrifuged at 1000 g at 4° C. for 10minutes, and the supernatant was then centrifuged at 20000 g at 4° C.for 20 minutes. The pellet was resuspended in incubation buffer (20 mMHEPES buffer (pH 7.4)) containing 10 mM glucose, 145 mM sodium chloride,4.5 mM potassium chloride, 1.2 mM magnesium chloride, and 1.5 mM calciumchloride) and used as crude synaptosome fraction.

The uptake reaction mixture was suspended in a final volume of 200 μlcontaining pargyline (final concentration of 10 μM) and sodium ascorbate(final concentration of 0.2 mg/ml) in each well of96-well-round-bottom-plate.

Solvent, unlabeled DA, and serial diluted test compounds were added ineach well, and synaptosome fraction of 1/10 volume of the final volumewere added. After 10-min preincubation at 37° C., the uptake wasinitiated by the addition of tritium labeled DA solution (finalconcentration of 2 nM) at 37° C. The uptake was stopped after 10 minutesby filtration under vacuum through a 96-well glass fiber filter plate.After washing the filter with cold physiological saline and drying up,Microscint-0 (Perkin-Elmer) was added and remained radioactivity on thefilter was measured.

The uptake activity with only solvent was determined as 100%, and thenonspecific uptake activity with unlabeled DA (final concentration of 10μM) was determined as 0%. The 50% inhibitory concentrations werecalculated based on the concentrations of the test compounds and theirinhibitory activities. Table 162 shows the results.

TABLE 162 Test Compound 50% inhibitory concentration (nM) Compound ofExample 7 45.0 Compound of Example 44 8.7 Compound of Example 46 9.3Compound of Example 73 9.0 Compound of Example 90 4.8 Compound ofExample 114 32.5 Compound of Example 116 8.9 Compound of Example 154 9.2Compound of Example 200 3.8 Compound of Example 201 4.3 Compound ofExample 268 6.5 Compound of Example 270 8.2 Compound of Example 272 30.0Compound of Example 273 32.9 Compound of Example 278 34.7 Compound ofExample 289 30.6 Compound of Example 294 24.0 Compound of Example 29948.6 Compound of Example 300 9.6 Compound of Example 894 9.4 Compound ofExample 895 38.0 Compound of Example 912 30.2 Compound of Example 9136.5 Compound of Example 930 6.8 Compound of Example 951 29.8 Compound ofExample 961 9.6 Compound of Example 963 47.1 Compound of Example 96725.4 Compound of Example 989 5.8 Compound of Example 990 26.0 Compoundof Example 1001 16.4 Compound of Example 1002 32.9

Pharmacological Test 4 Forced-Swimming Test

Forced-swimming test was conducted based on the method of Porsolt, R.D., et al. (Porsolt, R. D., et al., Behavioural despair in mice: Aprimary screening test for antidepressants. Arch. Int. Pharmacodyn.,229, pp 327-336 (1977) with a modification.

The test compound was suspended in a 5% gum arabic/physiological salinesolution (w/v) and then orally administered to male ICR mice (providedby Clea Japan Inc., 5 to 6 weeks old). One hour after administration,the mice were dropped into a tank containing 9.5 cm water maintained at21 to 25° C. Then, the mice were forced to swim for 6 minutes. Duringthe last four minutes of the test, the period of time the mice were notmoving was measured (i.e., immobility time). The analysis andmeasurement of the immobility time was conducted using a SCANET MV-20 AQsystem (product name of Melquest Co., Ltd.).

In this test, the test compound treated animal exhibited reduction ofimmobility time. Therefore it is clear that the test compound iseffective as an antidepressant.

1. A method for treating posttraumatic stress syndrome, comprisingadministering to a subject in need thereof an effective amount of apyrrolidine compound of General Formula (1)

or a salt thereof to human or animal, wherein R¹⁰¹ is (1) phenyl group,and R¹⁰² is one of the following groups (1) to (86): (1) a phenyl group,(2) a pyridyl group, (3) a benzothienyl group, (4) an indolyl group, (5)a 2,3-dihydro-1H-indenyl group, (6) a naphthyl group, (7) a benzofurylgroup, (8) a quinolyl group, (9) a thiazolyl group, (10) a pyrimidinylgroup, (11) a pyrazinyl group, (12) a benzothiazolyl group, (13) athieno[3,2-b]pyridyl group, (14) a thienyl group, (15) a cycloalkylgroup, (16) a tetrahydropyranyl group, (17) a pyrrolyl group, (18) a2,4-dihydro-1,3-benzodioxinyl group, (19) a 2,3-dihydrobenzofuryl group,(20) a 9H-fluorenyl group, (21) a pyrazolyl group, (22) a pyridazinylgroup, (23) an indolinyl group, (24) a thieno[2,3-b]pyridyl group, (25)a thieno[3,2-d]pyrimidinyl group, (26) a thieno[3,2-e]pyrimidinyl group,(27) a 1H-pyrazolo[3,4-b]pyridyl group, (28) an isoquinolyl group, (29)a 2,3-dihydro-1,4-benzoxadinyl group, (30) a quinoxalinyl group, (32) a1,2,3,4-tetrahydroquinolyl group, (33) a cycloalkyl lower alkyl group,(34) a lower alkylthio lower alkyl group, (35) an amino-substitutedlower alkyl group optionally substituted with one or two lower alkylgroups on the amino group, (36) a phenoxy lower alkyl group, (37) apyridyloxy lower alkyl group, (38) a lower alkynyl group, (39) a phenyllower alkenyl group, (40) a 1,3-benzodioxolyl group, (41) a2,3-dihydro-1,4-benzodioxinyl group, (42) a3,4-dihydro-1,5-benzodioxepinyl group, (43) a dihydropyridyl group, (44)a 1,2-dihydroquinolyl group, (45) a 1,2,3,4-tetrahydroisoquinolyl group,(46) a benzoxazolyl group, (47) a benzoisothiazolyl group, (48) anindazolyl group, (49) a benzoimidazolyl group, (50) an imidazolyl group,(51) a 1,2,3,4-tetrahydronaphthyl lower alkyl group, (54) atetrahydropyranyl lower alkyl group, (55) a piperidyl lower alkyl group,(56) a diphenyl lower alkoxy-substituted lower alkyl group, (57) a loweralkoxycarbonyl-substituted lower alkyl group, (58) a phenyl loweralkoxycarbonyl-substituted lower alkyl group, (59) a hydroxy-substitutedlower alkyl group, (60) a lower alkoxy lower alkyl group, (61) a carboxylower alkyl group, (62) a carbamoyl-substituted lower alkyl groupoptionally substituted with one or two lower alkyl groups on thecarbamoyl group, (63) a lower alkenyl group, (64) a morpholinylcarbonyllower alkyl group, (65) a benzoyl lower alkyl group, (66) a phenylthiolower alkyl group, (67) a naphthylthio lower alkyl group, (68) acycloalkylthio lower alkyl group, (69) a pyridylthio lower alkyl group,(70) a pyrimidinylthio lower alkyl group, (71) a furylthio lower alkylgroup, (72) a thienylthio lower alkyl group, (73) a1,3,4-thiadiazolylthio lower alkyl group, (74) a benzimidazolylthiolower alkyl group, (75) a benzthiazolylthio lower alkyl group, (76) atetrazolylthio lower alkyl group, (77) a benzoxazolylthio lower alkylgroup, (78) a thiazolylthio lower alkyl group, (79) an imidazolylthiolower alkyl group, (80) an amino-substituted lower alkylthio lower alkylgroup optionally substituted with one or two lower alkyl groups on theamino group, (81) a phenyl-substituted lower alkylthio lower alkylgroup, (82) a furyl-substituted lower alkylthio lower alkyl group, (83)a pyridyl-substituted lower alkylthio lower alkyl group, (84) ahydroxy-substituted lower alkylthio lower alkyl group, (85) aphenoxy-substituted lower alkylthio lower alkyl group, and (86) a loweralkoxycarbonyl-substituted lower alkylthio lower alkyl group, and eachof the groups (1) to (32), (37), (39) to (56), (64) to (79), (81) to(83) and (85) may have one or more substituents selected from thefollowing (1-1) to (1-37) on the cycloalkyl, aromatic or heterocyclicring: (1-1) halogen atoms, (1-2) lower alkylthio groups optionallysubstituted with one or more halogen atoms, (1-3) lower alkyl groupsoptionally substituted with one or more halogen atoms, (1-4) loweralkoxy groups optionally substituted with one or more halogen atoms,(1-5) nitro group, (1-6) lower alkoxycarbonyl groups, (1-7) amino groupsoptionally substituted with one or two lower alkyl groups, (1-8) loweralkylsulfonyl groups, (1-9) cyano group, (1-10) carboxy group, (1-11)hydroxy group, (1-12) thienyl groups, (1-13) oxazolyl groups, (1-14)naphthyl groups, (1-15) benzoyl group, (1-16) phenoxy groups optionallysubstituted with one to three halogen atoms on the phenyl ring, (1-17)phenyl lower alkoxy groups, (1-18) lower alkanoyl groups, (1-19) phenylgroups optionally substituted on the phenyl ring with one to fivesubstituents selected from the group consisting of halogen atoms, loweralkoxy groups, cyano group, lower alkanoyl groups and lower alkylgroups, (1-20) phenyl lower alkyl groups, (1-21) cyano lower alkylgroups, (1-22) 5 to 7-membered saturated heterocyclic group-substitutedsulfonyl groups, the heterocyclic group containing on the heterocyclicring one or two heteroatoms selected from the group consisting ofnitrogen, oxygen and sulfur, (1-23) thiazolyl groups optionallysubstituted with one or two lower alkyl groups on the thiazole ring,(1-24) imidazolyl groups, (1-25) amino lower alkyl groups optionallysubstituted with one or two lower alkyl groups on the amino group,(1-26) pyrrolidinyl lower alkoxy groups, (1-27) isoxazolyl groups,(1-28) cycloalkylcarbonyl groups, (1-29) naphthyloxy groups, (1-30)pyridyl groups, (1-31) furyl groups, (1-32) phenylthio group, (1-33) oxogroup, (1-34) carbamoyl group, (1-35) 5 to 7-membered saturatedheterocyclic groups containing one or two heteroatoms selected from thegroup consisting of nitrogen, oxygen and sulfur, the heterocyclic groupoptionally being substituted with one to three substituents selectedfrom the group consisting of oxo group; lower alkyl groups; loweralkanoyl groups; phenyl lower alkyl groups; phenyl groups optionallysubstituted on the phenyl ring with one to three members selected fromthe group consisting of halogen atoms and lower alkoxy groups; andpyridyl groups, (1-36) oxido group and (1-37) lower alkoxido groups,with the proviso that R101 and R102 are not simultaneously unsubstitutedphenyl.
 2. A process for producing a pyrrolidine compound of GeneralFormula (1) of claim 1:

or a salt thereof, the process comprising (1) subjecting a compound ofGeneral Formula (2)

wherein R¹⁰¹ and R¹⁰² are as defined in claim 13, and R¹¹² is anamino-protecting group to an elimination reaction to remove the aminoprotecting group.
 3. A method for treating posttraumatic stress syndromeaccording to claim 1, wherein in the pyrrolidine compound of GeneralFormula (1) or a salt thereof, R¹⁰¹ is (1) a phenyl group that may haveon the phenyl ring one to three substituents selected from the groups(1-1) to (1-37).
 4. A method for treating posttraumatic stress syndromeaccording to claim 3, wherein in the pyrrolidine compound of GeneralFormula (1) or a salt thereof, R¹⁰¹ is (1) a phenyl group that may haveon the phenyl ring one to three substituents selected from the groupconsisting of (1-1) halogen atoms and (1-3) lower alkyl groupsoptionally substituted with one to three halogen atoms.
 5. A method fortreating posttraumatic stress syndrome according to claim 4, wherein inthe pyrrolidine compound of General Formula (1) or a salt thereof, R¹⁰²is (1) a phenyl group, (2) a pyridyl group, (9) a thiazolyl group, (10)a pyrimidinyl group, (11) a pyrazinyl group, (14) a thienyl group, (48)an indazolyl group, (59) a hydroxy-substituted lower alkyl group or (60)a lower alkoxy lower alkyl group, and each of the groups (1), (2), (9),(10), (11), (14) and (48) may have on the phenyl or heterocyclic ringone to three substituents selected from the groups (1-1) to (1-37).
 6. Amethod for treating posttraumatic stress syndrome according to claim 5,wherein in the pyrrolidine compound of General Formula (1) or a saltthereof, R¹⁰¹ is a monohalophenyl group, a dihalophenyl group or aphenyl group substituted with one halogen atom and one lower alkylgroup, R¹⁰² is (1) a phenyl group, (2) a pyridyl group, (9) a thiazolylgroup, (10) a pyrimidinyl group, (11) a pyrazinyl group, (14) a thienylgroup, (48) an indazolyl group, (59) a hydroxy-substituted lower alkylgroup or (60) a lower alkoxy lower alkyl group, and each of the groups(1), (2), (9), (10), (11), (14) and (48) may have on the phenyl orheterocyclic ring one or two substituents selected from the groupconsisting of (1-1) halogen atoms, (1-3) lower alkyl groups optionallysubstituted with one or more halogen atoms, and (1-9) cyano group.
 7. Amethod for treating posttraumatic stress syndrome according to claim 5,wherein the pyrrolidine compound of General Formula (1) or a saltthereof is selected from the group consisting of:(4-chlorophenyl)phenyl-(S)-pyrrolidin-3-ylamine,(4-fluorophenyl)phenyl-(S)-pyrrolidin-3-ylamine,(3,4-difluorophenyl)phenyl-(S)-pyrrolidin-3-ylamine,bis-(4-fluorophenyl)-(S)-pyrrolidin-3-ylamine,(3,4-difluorophenyl)-(4-fluorophenyl)-(S)-pyrrolidin-3-ylamine,(3-chloro-4-fluorophenyl)-(S)-pyrrolidin-3-yl-p-tolylamine,4-[(S)-(4-fluoro-3-methylphenyl)pyrrolidin-3-ylamino]-benzonitrile,bis-(3-fluorophenyl)-(S)-pyrrolidin-3-ylamine,(3-chloro-4-fluorophenyl)-(S)-pyrrolidin-3-ylthiazol-2-ylamine,(4-fluorophenyl)-(S)-pyrrolidin-3-ylthiazol-2-ylamine,(3,4-dichlorophenyl)-(S)-pyrrolidin-3-ylthiazol-2-ylamine,(3,4-dichlorophenyl)pyrimidin-5-yl-(S)-pyrrolidin-3-ylamine,(3-chloro-4-fluorophenyl)pyrazin-2-yl-(S)-pyrrolidin-3-ylamine,(3-chloro-4-fluorophenyl)-(5-chloropyridin-2-yl)-(S)-pyrrolidin-3-ylamine,(3-chloro-4-fluorophenyl)pyridin-2-yl-(S)-pyrrolidin-3-ylamine,(3-chloro-4-fluorophenyl)pyridin-3-yl-(S)-pyrrolidin-3-ylamine,(3-chloro-4-fluorophenyl)-(6-fluoropyridin-3-yl)-(S)-pyrrolidin-3-ylamine,(3,4-dichlorophenyl)pyridin-3-yl-(S)-pyrrolidin-3-ylamine,(3-chloro-4-fluorophenyl)-(S)-pyrrolidin-3-ylthiophen-3-ylamine,(3-chloro-4-fluorophenyl)-(5-fluoropyridin-3-yl)-(S)-pyrrolidin-3-ylamine,(4-fluoro-3-methylphenyl)-(5-fluoropyridin-3-yl)-(S)-pyrrolidin-3-ylamine,2-[(S)-(3-chloro-4-fluorophenyl)pyrrolidin-3-ylamino]ethanol,1-[(S)-(3-chloro-4-fluorophenyl)pyrrolidin-3-ylamino]-2-methyl-propan-2-ol,(3-chloro-4-fluorophenyl)-(2-methoxyethyl)-(S)-pyrrolidin-3-ylamine,3-[(S)-(3-chloro-4-fluorophenyl)pyrrolidin-3-ylamino]-propan-1-ol,(3-chloro-4-fluorophenyl)-(3-methoxypropyl)-(S)-pyrrolidin-3-ylamine,(3-chloro-4-fluorophenyl)-(1-methyl-1H-indazol-5-yl)-(S)-pyrrolidin-3-ylamine,and the salts thereof.